[Imaging prior to transcatheter aortic valve implantation]. / Bildgebung vor Transkatheteraortenklappenersatz.

Percutaneous transcatheter aortic valve implantation (TAVI) is an established alternative to open heart surgery in patients with severe aortic stenosis (AS) unsuitable for conventional aortic valve replacement due to comorbidities with a high perioperative risk or contraindications. Preprocedural imaging plays a major role for adequate determination of indications and prosthesis selection, prosthesis sizing and therefore for a reduction of periprocedural complications. Besides Doppler echocardiography which is mainly used for grading of the severity of aortic valve stenosis and peri-interventional imaging, cardiac computed tomography (CCT) is the imaging modality of choice. The CCT procedure not only allows for reliably assessment and measuring of the complex 3-dimensional geometry of the aortic root but also for the aorta and the peripheral vessels used as potential access paths.

Role of preprocedural computed tomography in transcatheter aortic valve implantation.

UNLABELLED: Transcatheter aortic valve implantation (TAVI) is currently considered an acceptable alternative for the treatment of patients with severe aortic stenosis and a high perioperative risk or a contraindication for open surgery. The benefit of TAVI significantly outweighs the risk of the procedure in patients requiring treatment that are not suitable for open surgery, and leads to a lower mortality in the one-year follow-up. The absence of a direct view of the aortic root and valve remains a challenge for the transcatheter approach. While direct inspection of the aortic valve during open surgery allows an adequate prosthesis choice, it is crucial for TAVI to know the individual anatomical details prior to the procedure in order to assure adequate planning of the procedure and proper prosthesis choice and patient selection. Among the imaging modalities available for the evaluation of patients prior to TAVI, computed tomography (CT) plays a central role in patient selection. CT reliably visualizes the dimensions of the aortic root and allows a proper choice of the prosthesis size. The morphology of the access path and relevant comorbidities can be assessed. The present review summarizes the current state of knowledge regarding the value of CT in the evaluation of patients prior to TAVI. KEY POINTS: CT plays a central role in patient selection and planning prior to TAVI. ▶ CT reliably detects the dimensions of the aortic root including the size of the aortic annulus, the degree of valve calcification and the morphology of the access routes. ▶ CT provides a more accurate measurement of the aortic annulus than 2D TEE and CT is the only imaging modality that allows a risk assessment for paravalvular leakages based on the calcification of the aortic valve.

Experience with anatomically orientated devices for transapical aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is a new technology, which is rapidly growing to a routine procedure amenable for patients with symptomatic aortic valve stenosis and higher than average risk for conventional aortic valve surgery. The crucial disadvantage of TAVI remains the not well foreseeable risk of more than trivial degree of paravalvular leakage and a high rate of atrioventricular block and consecutive pacemaker implantation. In addition, current implantation techniques do not allow controlling the rotation of first-generation devices that might be beneficial regarding optimal physiological valve performance, optimal coronary flow and avoidance of placement of covered commissures in front of the coronary ostia. These shortcomings had pushed the development of second-generation self-expandable nitinol-based devices for subcoronary implantation that aim a reduction of paravalvular leak and AV-block by anatomical orientated positioning into the aortic root. This review focuses on the description of three different TAVI concepts, which are presently under early clinical evaluation, or have recently received commercial approval, using the transapical approach.

Role of preprocedural computed tomography in transcatheter aortic valve implantation.

UNLABELLED: Transcatheter aortic valve implantation (TAVI) is currently considered an acceptable alternative for the treatment of patients with severe aortic stenosis and a high perioperative risk or a contraindication for open surgery. The benefit of TAVI significantly outweighs the risk of the procedure in patients requiring treatment that are not suitable for open surgery, and leads to a lower mortality in the one-year follow-up. The absence of a direct view of the aortic root and valve remains a challenge for the transcatheter approach. While direct inspection of the aortic valve during open surgery allows an adequate prosthesis choice, it is crucial for TAVI to know the individual anatomical details prior to the procedure in order to assure adequate planning of the procedure and proper prosthesis choice and patient selection. Among the imaging modalities available for the evaluation of patients prior to TAVI, computed tomography (CT) plays a central role in patient selection. CT reliably visualizes the dimensions of the aortic root and allows a proper choice of the prosthesis size. The morphology of the access path and relevant comorbidities can be assessed. The present review summarizes the current state of knowledge regarding the value of CT in the evaluation of patients prior to TAVI. CT plays a central role in patient selection and planning prior to TAVI. CT reliably detects the dimensions of the aortic root including the size of the aortic annulus, the degree of valve calcification and the morphology of the access routes. KEY POINTS: CT plays a central role in patient selection and planning prior to TAVI. CT reliably detects the dimensions of the aortic root including the size of the aortic annulus, the degree of valve calcification and the morphology of the access routes. CT provides a more accurate measurement of the aortic annulus than 2D TEE and CT is the only imaging modality that allows a risk assessment for paravalvular leakages based on the calcification of the aortic valve.

A portable Compton spectrometer for clinical X-ray beams in the energy range 20-150 keV.

Primary beam spectra were obtained for an X-ray industrial equipment (40-150 kV), and for a clinical mammography apparatus (25-35 kV) from beams scattered at angles close to 90°, measured with a CdTe Compton spectrometer. Actual scattering angles were determined from the Compton energy shift of characteristic X-rays or spectra end-point energy. Evaluated contribution of coherent scattering amounts to more than 15% of fluence in mammographic beams. This technique can be used in clinical environments.

Metabolic profile and nitric oxide synthase expression of skeletal muscle fibers are altered in patients with type 1 diabetes.

We investigate muscle fiber composition, fiber-specific glycolytic and oxidative enzyme capacity and nitric oxide synthase (NOS) expression in skeletal muscle of patients with type 1 diabetes (T1D) compared to individuals with normal glucose tolerance (NGT). Vastus lateralis muscle was obtained by percutaneous biopsy from 7 T1D patients and 10 healthy controls with similar characteristics. Using cytophotometry, muscle fiber composition and fiber type-specific glycolytic and oxidative enzyme activities were measured in slow oxidative (SO), fast oxidative glycolytic (FOG) and fast glycolytic (FG) fibers. In addition, NOS 1-3 protein expression was mea-sured. The glycolytic fiber fraction was 1.4 fold higher, whereas FOG and SO fiber fractions were significantly reduced by 13.5% and 6.2% in skeletal muscle from T1D patients. Glycolytic enzyme activities and fiber-specific ratio of glycolytic relative to oxidative enzyme activity were significantly higher in all fiber types of T1D patients and correlated with HbA (1c). Expression of NOS1-3 isoforms was reduced in skeletal muscle of T1D subjects. Increased glycolytic enzyme activity in muscle of T1D patients is most likely due to both a higher number of fast glycolytic fibers and a shift towards increased glycolytic metabolism in all fiber types. Alterations in muscle fiber distribution and enzyme activities seem to be due to impaired long-term glycemic control.

Adipokines in diabetes and cardiovascular diseases.

Recent studies suggest that adipocyte-secreted factors called adipokines are involved in obesity-associated complications including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Among those, adiponectin is an antidiabetic and antiatherogenic protein, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. In contrast, leptin, tumor necrosis factor a, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 are upregulated in obesity and contribute to the development of diabetes and vascular disease. In this review, the relevance of adipokines in obesity, insulin resistance, diabetes mellitus, atherosclerosis, and cardiovascular diseases is discussed.

Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia.

AIMS: Despite considerable advances in the therapy of patients with peripheral arterial occlusive disease (PAOD) and critical limb ischaemia (CLI), a substantial number remain, in whom amputation has to be considered the only and final option. Recent evidence from animal models of hind limb ischaemia suggests that neovascularization induced by circulating blood-derived progenitor cells (CPCs) may permit limb salvage. It remains unclear, however, whether an intra-arterial application of autologous CPCs in patients with infrapopliteal PAOD and CLI is safe, feasible, and of potentially beneficial effects. METHODS AND RESULTS: Seven patients with critical PAOD were treated with an intra-arterial infusion of autologous CPCs (39+/-24 x 10(6)) isolated from peripheral blood. Pre-interventional stimulation with G-CSF and CPC application was well tolerated. Twelve weeks after CPC administration, the pain-free walking distance increased from 6+/-13 to 195+/-196 m. A significant increase in the ankle-brachial index, transcutaneous O(2), flow-dependent vasodilation, flow reserve in response to adenosine, and endothelium-dependent vasodilation was observed. CONCLUSION: These preliminary data in a small series of patients with CLI without surgical or interventional options indicate that CPC application is safe, feasible, and may improve both functional and clinical indices.

Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase.

BACKGROUND: In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD. METHODS AND RESULTS: In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser1177, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56+/-8% (from +48+/-8% at beginning to +104+/-11% after 4 weeks, P<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0+/-0.7 versus C 0.5+/-0.3 arbitrary units, P<0.05) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium (1.2+/-0.9 versus 0.3+/-0.2 arbitrary units, P<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (R=0.80, P<0.05) and between phospho-eNOS and Delta APV (R=0.59, P<0.05). CONCLUSIONS: Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Akt-dependent phosphorylation of eNOS on Ser1177.

Strain specific variation in cytokine regulated ICAM-1 expression by rat brain-endothelial cells.

Cytokine induced levels of ICAM-1 expressed by rat brain-endothelial cells were quantitated by enzyme immunoassay in response to stimulation by TNF-alpha in the presence or absence of IFN-gamma. The rat strains investigated differ in their susceptibility to experimental allergic encephalomyelitis; significantly less ICAM-1 was induced by BEC derived from the resistant PVG strain as compared to the susceptible LEW strain with both cytokine combinations. In contrast, despite the difference in disease susceptibility, equivalent levels of ICAM-1 were induced between the LEW and BN strain. Furthermore, evidence for a synergistic interaction of both TNF-alpha and IFN-gamma was observed in the BN strain. The results are discussed with relevance to the disease profile of each strain.

Effect of exercise on coronary endothelial function in patients with coronary artery disease.

BACKGROUND: Studies of the cardioprotective effects of exercise training in patients with coronary artery disease have yielded contradictory results. Exercise training has been associated with improvement in myocardial perfusion even in patients who have progression of coronary atherosclerosis. We therefore conducted a prospective study of the effect of exercise training on endothelial function in patients with coronary artery disease. METHODS: We randomly assigned 19 patients with coronary endothelial dysfunction, indicated by abnormal acetylcholine-induced vasoconstriction, to an exercise-training group (10 patients) or a control group (9 patients). To reduce confounding, patients with coronary risk factors that could be influenced by exercise training (such as diabetes, hypertension, hypercholesterolemia, and smoking) were excluded. In an initial study and after four weeks, the changes in vascular diameter in response to the intracoronary infusion of increasing doses of acetylcholine (0.072, 0.72, and 7.2 microg per minute) were assessed. The mean peak flow velocity was measured by Doppler velocimetry, and the diameter of epicardial coronary vessels was measured by quantitative coronary angiography. RESULTS: In the initial study, the two groups had similar vasoconstrictive responses to acetylcholine. After four weeks of exercise training, coronary-artery constriction in response to acetylcholine at a dose of 7.2 microg per minute was reduced by 54 percent (from a mean [+/-SE] decrease in the luminal diameter of 0.41+/-0.05 mm in the initial study to a decrease of 0.19+/-0.07 mm at four weeks; P<0.05 for the comparison with the change in the control group). In the exercise-training group, the increases in mean peak flow velocity in response to 0.072, 0.72, and 7.2 microg of acetylcholine per minute were 12+/-7, 36+/-11, and 78+/-16 percent, respectively, in the initial study. After four weeks of exercise, the increases in response to acetylcholine were 27+/-7, 73+/-19, and 142+/-28 percent (P<0.01 for the comparison with the control group). Coronary blood-flow reserve (the ratio of the mean peak flow velocity after adenosine infusion to the resting velocity) increased by 29 percent after four weeks of exercise (from 2.8+/-0.2 in the initial study to 3.6+/-0.2 after four weeks; P<0.01 for the comparison with the control group). CONCLUSIONS: Exercise training improves endothelium-dependent vasodilatation both in epicardial coronary vessels and in resistance vessels in patients with coronary artery disease.

Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance.

OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.

Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle.

OBJECTIVES: This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF). BACKGROUND: The molecular mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance. METHODS: Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incubated with sodium nitroprusside (SNP). RESULTS: Expression of iNOS was significantly increased in CHF (4.0+/-2.8 vs. 0.8+/-0.7% iNOS positive tissue area, p < 0.001 vs. C) and inversely correlated to maximal oxygen uptake (r=-0.65, p < 0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5+/-8.5 vs. 2.0+/-1.7% NT-positive tissue area, p < 0.001 vs. C). Mi-CK was decreased in CHF (0.84+/-0.36 vs. 1.57+/-0.60, p < 0.001 vs. C). The inverse correlation seen between iNOS and mi-CK expression in patients (r=-0.68, p < 0.001) was reproduced in incubation experiments with SNP. CONCLUSIONS: Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.

Leukocytopenia, thrombocytopenia and fever related to piperacillin/tazobactam treatment--a retrospective analysis in 38 children with cystic fibrosis.

Bone marrow suppression is an important adverse reaction to most betalactam antibiotics. Recently it was suggested that piperacillin/tazobactam (PT) also may cause bone marrow toxicity. We retrospectively analyzed 100 i.v. antibiotic treatment courses (mean duration 12.5 days) in 38 patients (median age 14 years) with cystic fibrosis (CF) who were treated in our hospital. Of the patients receiving PT (84%), 6 patients (18.75% of PT-treated patients, 10.3% of PT treatment courses) developed fever, malaise and headache during treatment without signs of acute infection. In one patient definite thrombocytopenia and neutropenia, in two others a milder decrease in leukocyte and thrombocyte counts was observed after the onset of fever. The events were time- and dose-dependent occurring between day 11 and 15 of treatment. Treatment courses lasted longer (14.2 vs 11.3 days; p < 0.05) and patients had received a higher cumulative dose of PT (4919 +/- 1975 mg/kg b.w. vs 3161 +/- 1635 mg/kg; p < 0.02, Student's t-test) in the affected group than in the unaffected group. After discontinuation of PT, fever subsided within 24 h and blood cell counts normalized. We hypothesize that these fever episodes and changes of blood parameters are related to PT therapy.

Increased inducible nitric oxide synthase in skeletal muscle biopsies from patients with chronic heart failure.

In addition to left ventricular pump failure and low cardiac output, structural and metabolic alterations of skeletal muscle are thought to contribute to exercise intolerance seen in patients with CHF. Studies using cardiac myocytes have implicated nitric oxide elaborated by inducible nitric oxide synthase (iNOS) as a potential agent associated with the genesis of dilated cardiomyopathy. The present study was designed to locate iNOS in the working skeletal muscle of patients with congestive heart failure. Specific antibodies were used to detect iNOS by immunohistochemistry in skeletal muscle biopsies (m. vastus lateralis) of 37 patients with left ventricular pump failure and 8 normal controls. The expression was restricted to skeletal muscle myocytes and was increased five- to ninefold in patients with chronic heart failure. There was no statistically significant difference in iNOS expression between patients with dilated cardiomyopathy and those with ischemic cardiomyopathy. The finding of a locally increased expression of iNOS and the experimental evidence that NO attenuates the contractile performance of the skeletal muscle suggest that the expression of iNOS may be responsible for the exercise intolerance seen in patients with chronic heart failure.

Nonexpression of CD15 by neoplastic glia: a barrier to metastasis?

Cluster of differentiation 15 (CD15) monoclonal antibodies recognise cell adhesion molecules on the surface of many cells including normal astrocytes and metastatic carcinoma cells. The CD15 epitope (fucosyl-N-acetyl-lactosamine), an adhesive oligosaccharide, functions as a ligand for the selectin family of membrane receptors. These include CD62, a cytokineinducible glycoprotein found in platelets and endothelial cells. CD15 is one of a series of putative adhesion molecules expressed in nervous tissue. Selectin-carbohydrate interactions have been implicated in the metastatic spread of cancer cells. We have immunostained a variety of cultured human brain tumours, three cell lines derived from experimental rat gliomas, two specimens of cultured human foetal astrocytes, two metastatic carcinoma cell lines and human umbilical vein endothelial cells (HUVEC) using two monoclonal antibodies which recognise CD15. While all of the animal glioma cells were positive for CD15, only two human glioma cell lines, derived from an anaplastic astrocytoma and a glioblastoma multiforme, respectively, displayed limited reactivity. Chromium radiolabel binding assays of CD15-positive and -negative cell lines including glioma and carcinoma-derived cells, using HUVEC as an attachment substrate, were carried out in the presence and absence of CD15 monoclonal antibody. The level of adhesion of neoplastic cells to HUVEC not only corresponded to CD 15 expression but application of anti-CD 15 monoclonal antibodies considerably reduced adhesion. We postulate that the absence of CD15 on human glioma cells may explain, to some extent, the general failure of intrinsic brain tumours to metastasis by precluding the adhesion of circulating neoplastic glia to 'target' organ endothelium.

An interferon-inducible molecule on brain endothelium which controls lymphocyte adhesion mediated by integrins.

We undertook a search for cytokine-inducible molecules present on brain endothelium and which are involved in the control of lymphocyte adhesion. We screened 39 monoclonal antibodies (mAb) against rat brain endothelium in vitro, and identified five recognizing cytokine-inducible molecules. None of the 39 antibodies blocked lymphocyte adhesion, but one antibody (4A2), produced a 400% enhancement of lymphocyte binding. The 4A2 antigen is induced on brain endothelium by interferon-gamma (INF-gamma) but not tumour necrosis factor-alpha (TNF-alpha), at 6-48 hr. It is preferentially expressed near inter-endothelial cell junctions, but it also expressed on all lymphocytes and weakly on aortic endothelium in vitro. In vivo, it is not detectable on cells in the normal central nervous system (CNS), however it appears in the CNS during T-cell mediated immune reactions. Triggering of cells via this molecule enhances integrin-mediated adhesion of lymphocytes to brain endothelium, primarily via LFA-1. Unlike ICAM-1, 4A2 antigen is induced on endothelium of both Lewis and PVG strains. Although, it has some functional properties of human CD31, the 4A2 antigen is not rat CD31. The cellular localization of this molecule, its actions on integrin-mediated adhesion and its induction by IFN-gamma, all indicate that the 4A2 antibody recognizes a molecule involved in the control of lymphocyte migration into the brain.