Is the diagnostic yield of myocardial stress perfusion MRI impaired by three-vessel coronary artery disease?

BACKGROUND: Three-vessel coronary artery disease (CAD) comes along with globally reduced myocardial perfusion potentially restricting the demarcation of regional hypoperfusion in stress perfusion cardiac magnetic resonance imaging (MRI). PURPOSE: To evaluate whether stress perfusion cardiac MRI is capable of detecting myocardial hypoperfusion in patients with 3-vessel CAD reliably. MATERIAL AND METHODS: Two hundred and five patients with symptoms of CAD were included. The examination protocol comprised imaging of myocardial perfusion at stress (0.14 mg/kg/min adenosine for 4 min) using a 2D saturation recovery gradient echo sequence after administration of gadobutrol (0.1 mmol/kg body weight). Perfusion sequences were assessed qualitatively by two experienced observers. Coronary angiography served as standard of reference. RESULTS: Sensitivity and specificity for hemodynamically relevant stenoses in patients with 0-, 1-, 2-, 3-vessel coronary artery disease were 100%/91%, 91%/73%, 90%/71%, 92%/64%; positive/negative predictive value, 67%/100%, 91%/73%, 83%/81%, 93%/58%; diagnostic accuracy, 93%/87%/83%/87%, respectively. The negative predictive value in patients with 3-vessel CAD was lower than in patients with 0- and 2-vessel CAD and the specificity lower than in patients with no CAD whereas the positive predictive value was higher than in patients with no CAD. The other proportions did not differ significantly between the groups. CONCLUSION: The diagnostic value of stress perfusion cardiac MRI in patients with 3-vessel CAD is comparable to results in patients with 1- or 2-vessel CAD. In the rare event that stress perfusion images do not depict regional hypoperfusion in patients with severe 3-vessel CAD, myocardial ischemia could be identified by reduced semi-quantitative perfusion parameters.

Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia.

The contribution of BRCA1/BRCA2 mutations to hereditary breast cancer in the Tunisian population has not been accurately estimated. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in early onset and familial breast/ovarian cancer among Tunisian women. To identify predictive factors for BRCA1/2 mutations, we screened the entire coding sequences and intron/exon boundaries of BRCA1/BRCA2 genes in 48 patients by direct sequencing. Twelve pathogenic mutations were detected (25%); three in BRCA1 (c.211dupA in four families, c.5266dupC in three families and c.1504_1508delTTAAA in one family) and two novel mutations in BRCA2 (c.1313dupT in two families and c.7654dupT in two families). We also identified 23 different polymorphisms and unclassified variants. These results indicate that our population has a spectrum of recurrent BRCA mutations.

Platelets and matrix metalloproteinases.

Matrix metalloproteinases (MMPs) and their inhibitors essentially contribute to a variety of pathophysiologies by modulating cell migration, tissue degradation and inflammation. Platelet-associated MMP activity appears to play a major role in these processes. First, platelets can concentrate leukocyte-derived MMP activity to sites of vascular injury by leukocyte recruitment. Second, platelets stimulate MMP production in e.g. leukocytes, endothelial cells, or tumour cells by direct receptor interaction or/and by paracrine pathways. Third, platelets synthesise and secrete a variety of MMPs including MMP-1, MMP-2, MMP-3, and MMP-14 (MT1-MMP), and potentially MMP-9 as well as the tissue inhibitors of metalloproteinase (TIMPs). This review focuses on platelet-derived and platelet-induced MMPs and their inhibitors.

Expression of stromal-cell-derived factor-1 (SDF-1): a predictor of ischaemic stroke?

BACKGROUND AND PURPOSE: Platelet stromal-cell-derived factor-1 (SDF-1) plays a pivotal role in angiogenesis and the regeneration of ischaemic tissue through the regulation of haematopoietic progenitor cells and is upregulated at the sites of vascular injury and platelet activation. Thus, SDF-1 has recently been discussed as a predictor in ischaemic diseases such as acute myocardial infarction. However, no clinical data pertinent to the investigation of the platelet SDF-1 expression in patients with stroke are available. METHODS: We consecutively evaluated 196 patients who were admitted to the stroke unit with symptoms suspected for stroke. Surface expression of the platelet activation markers (P-selectin and GPIb) and the expression of platelet-bound SDF-1 were determined by two-colour whole blood flow cytometry. RESULTS: Patients with transient ischaemic attack (TIA) as well as with ischaemic stroke showed similar levels of SDF-1 expression on hospital admission compared with patients with non-ischaemic (NI) events and with 30 healthy controls (TIA (mean fluorescence intensity±SD): 31.5±18.2 vs. NI: 26.4±15.7; P=0.361; stroke: 28.7±19.8 vs. NI; P=0.943; control: 26.1±11.3; P>0.05 compared with all). Platelet SDF-1 expression showed a trend with the severity of stroke according to National Institute of Health Stroke Scale score (r=0.125; P=0.085), but significantly correlated with the peak levels of C-reactive protein (r=0.218; P=0.002) and with the levels of platelet activation (P-selectin: r=0.389; P=0.001). Multifactorial analysis of covariance revealed a significant influence on platelet SDF-1 expression by smoking (P=0.019). CONCLUSIONS: Platelet SDF-1 surface expression did not show any significant difference in patients with TIA and ischaemic stroke compared with patients with NI events. Thus, single biomarker evaluation of platelet SDF-1 surface expression is not helpful to predict ischaemic stroke.

[Recurrent pericardial effusion as first manifestation of Erdheim-Chester disease]. / Rezidivierender Perikarderguss als Erstmanifestation eines Morbus Erdheim-Chester.

HISTORY AND ADMISSION FINDINGS: A 65-year-old woman presented with reduced general condition and dyspnoea that was progressive over the last months. Clinical findings revealed an exophthalmus on the right, xanthelasm and mild peripheral oedema. Previously, a pericardiocentesis had been performed due to a large pericardial effusion. A previous CT scan showed a mass attached to the pericardium extending through the atrio-ventricular groove and a thickened aorta. In addition, a retroperitoneal fibrosis and an occlusion of both Aa. iliacae internae were found. INVESTIGATIONS: The ECG showed sinus rhythm. Laboratory findings demonstrated a microcytic anemia and a renal failure. Chest radiography showed a large cardiac silhouette, while the transthoracic echocardiography revealed a recurrent large pericardial effusion. A PET/CT scan of the chest and abdomen showed a tissue infiltration of the retroperitoneal structures, a mass surrounding the right coronary artery and the right orbita. Finally, a femur biopsy confirmed the diagnosis of Erdheim-Chester disease. DIAGNOSIS, TREATMENT AND COURSE: With the diagnosis Erdheim-Chester disease we started a high dose immunsuppressive therapy using glucocorticoids and interferon-a. Tumour size slightly decreased during the following 2 months, however the patient developed a severe urosepsis and died from multiorgan failure. CONCLUSIONS: We report a case of an Erdheim-Chester disease with cardiovascular involvement primarily diagnosed due to a recurrent large pericardial effusion. In case of cardial tumors with interatrial septum or coronary artery involvement together with cerebral manifestations, an Erdheim-Chester disease should be taken into account.

[Acute thrombo-embolic elevated ST infarct in a patient with essential thrombocytosis]. / Akuter thrombembolischer ST-Hebungs-Infarkt bei einem Patienten mit essenzieller Thrombozytose.

A 48-year-old man presented with acute chest pain and a greatly increased platelet count. Emergency coronary angiographic revealed thrombotic occlusion of the right coronary artery. Coronary angioplasty and stenting were successfully combined with intracoronary abciximab administration. Due to inadequate postinterventional platelet inhibition an intensified dual antiplatelet therapy with acetylsalicylic acid (ASS) and clopidogrel was applied to prevent stent thrombosis. Due to the thrombo-embolic complication and a platelet count over 1 million/microl a cytoreductive treatment with hydroxyurea was initiated.

[MR stress perfusion for the detection of flow-limiting stenoses in symptomatic patients with known coronary artery disease and history of stent implantation]. / MR-Stressperfusion zur Vorhersage flusslimitierender Stenosen bei symptomatischen Patienten mit bekannter KHK nach Stentimplantation.

PURPOSE: The aim of the present study was to determine the correlation of myocardial perfusion MR imaging (MPMRI) and coronary angiography for the detection of flow-limiting stenosis in symptomatic patients with known coronary artery disease and a history of intervention. MATERIALS AND METHODS: MPMRI was performed in 51 symptomatic patients (44 male, 64.7 +/- 9.5 years) with known coronary artery disease and a history of stent implantation (between 5 years and 2 weeks prior to MRI). Malperfused myocardial regions were correlated with findings of coronary angiography. A stenosis of > 70% was regarded as hemodynamically significant. RESULTS: In MPMRI 37 patients (73%) showed a stress induced perfusion deficit. In 35 of these patients coronary angiography revealed a stenosis of > 70 %. A total of 38 patients (75%) showed stenoses of > 70%. MPMRI yielded a sensitivity of 92% with a specificity of 85 %. The positive predictive value was 95 % and negative predictive value was 79%. The assignment of malperfused segments to coronary artery territories was carried out according to the standardized myocardial model of the American Heart Association (sensitivity/specificity was 59/85% for RCA, 79/81% for LAD and 54/68 % for LCX). CONCLUSION: MPMRI is a suitable non-invasive method for detecting flow-limiting coronary artery stenoses in patients with a history of stent implantation.

Uncorrected total anomalous pulmonary venous drainage in pregnancy.

Total anomalous pulmonary venous drainage is a rare form of congenital heart disease. It usually presents in the neonatal period, although later presentation, including in adulthood, is known to occur. We could not find any accounts of adult survivors with the undiagnosed disease becoming pregnant. We describe the case of a 19-year-old Bengali primiparous woman who arrived in the UK at 27 weeks' gestation and needed an urgent caesarean section for intrauterine growth restriction at 34 weeks' gestation. Uncorrected congenital heart disease was diagnosed at this time although the exact nature of the pathology was not clear. She underwent an uncomplicated caesarean section using a combined spinal-epidural technique with invasive monitoring. Intrathecal 0.5% hyperbaric bupivacaine 0.7 mL and fentanyl 25 microg were sufficient for surgery. She remained cardiovascularly stable throughout the procedure and a female infant was successfully delivered. She underwent corrective cardiac surgery 14 months after delivery. To our knowledge, this is the first report of caesarean section in a patient with uncorrected total anomalous pulmonary venous drainage. In this case, regional anaesthesia was successfully used.

Haemostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation.

Vascular cell adhesion and migration, proliferation or differentiation are cellular responses that are induced by haemostatic factors of the urokinase/plasminogen activation complex, but the respective underlying mechanisms are largely undefined. The direct and indirect contributions of the urokinase-type plasminogen activator receptor (uPAR) system in inflammatory processes, as they relate to recruitment of leukocytes, define novel functions and could serve as therapeutic targets for related vasculopathies. The presence of uPAR plays a crucial role in beta2-integrin-mediated adhesion of leukocytes; uPAR also directly mediates leukocyte adhesion to vitronectin, a multifunctional adhesion protein that is associated with the extracellular matrix. The latter process is inhibited by plasminogen activator inhibitor-1. Both beta2-integrin- and uPAR-dependent processes are activated by Zn2+ and are blocked by high-molecular-mass kininogen. Domain 5 of kininogen was identified, in particular, as an anti-adhesive component with a potent anti-inflammatory action in a peritonitis mouse model. In patients with acute myocardial infarction, elevated expression of uPAR on monocytes resulted in their increased adherence to the endothelium, which indicates a possible role of the uPAR system in monocyte recruitment to the infarcted area. Urokinase-type plasminogen activator was identified as a potent mitogen for vascular smooth muscle cells, an observation that was independent of the presence of uPAR and its proteolytic activity. Taken together, these results strongly suggest an essential role for the uPAR system in acute inflammation as well as in chronic degenerative vascular processes such as atherosclerosis. Targeting the uPAR system may allow specific therapeutic intervention in vascular pathologies.

Regulation of leukocyte recruitment by polypeptides derived from high molecular weight kininogen.

Proteolytic cleavage of single-chain, high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind a two-chain, high molecular weight kininogen (HKa) reported to bind to the beta2-integrin Mac-1 (CR3, CD11b/CD18, alphaMbeta2) on neutrophils and exert antiadhesive properties by binding to the urokinase receptor (uPAR) and vitronectin. We define the molecular mechanisms for the antiadhesive effects of HK related to disruption of beta2-integrin-mediated cellular interactions in vitro and in vivo. In a purified system, HK and HKa inhibited the binding of soluble fibrinogen and ICAM-1 to immobilized Mac-1, but not the binding of ICAM-1 to immobilized LFA-1 (CD11a/CD18, alphaLbeta2). This inhibitory effect could be attributed to HK domain 5 and to a lesser degree to HK domain 3, consistent with the requirement of both domains for binding to Mac-1. Accordingly, HK, HKa, and domain 5 inhibited the adhesion of Mac-1 but not LFA-1-transfected K562 human erythroleukemic cells to ICAM-1. Moreover, adhesion of human monocytic cells to fibrinogen and to human endothelial cells was blocked by HK, HKa, and domain 5. By using peptides derived from HK domain 5, the sequences including amino acids H475-G497 (and to a lesser extent, G440-H455) were identified as responsible for the antiadhesive effect, which was independent of uPAR. Finally, administration of domain 5 into mice, followed by induction of thioglycollate-provoked peritonitis, decreased the recruitment of neutrophils by approximately 70% in this model of acute inflammation. Taken together, HKa (and particularly domain 5) specifically interacts with Mac-1 but not with LFA-1, thereby blocking Mac-1-dependent leukocyte adhesion to fibrinogen and endothelial cells in vitro and in vivo and serving as a novel endogenous regulator of leukocyte recruitment into the inflamed tissue.

Urokinase receptor: a molecular organizer in cellular communication.

In a variety of cell types, the glycolipid-anchored urokinase receptor (uPAR) is colocalized pericellularly with components of the plasminogen activation system and endocytosis receptors. uPAR is also coexpressed with caveolin and members of the integrin adhesion receptor superfamily. The formation of functional units with these various proteins allows the uPAR to mediate the focused proteolysis required for cell migration and invasion and to contribute both directly and indirectly to cell adhesive processes in a non-proteolytic fashion. This dual activity, together with the initiation of signal transduction pathways by uPAR, is believed to influence cellular behaviour in angiogenesis, inflammation, wound repair and tumor progression/metastasis and open up the way for uPAR-based therapeutic approaches.

VLA-4 (alpha(4)beta(1)) engagement defines a novel activation pathway for beta(2) integrin-dependent leukocyte adhesion involving the urokinase receptor.

During acute inflammatory processes, beta(2) and beta(1) integrins sequentially mediate leukocyte recruitment into extravascular tissues. We studied the influence of VLA-4 (very late antigen-4) (alpha(4)beta(1)) engagement on beta(2) integrin activation-dependent cell-to-cell adhesion. Ligation of VLA-4 by the soluble chimera fusion product vascular cell adhesion molecule-1 (VCAM-1)-Fc or by 2 anti-CD29 (beta(1) chain) monoclonal antibodies (mAb) rapidly induced adhesion of myelomonocytic cells (HL60, U937) to human umbilical vein endothelial cells (HUVECs). Cell adhesion was mediated via beta(2) integrin (LFA-1 and Mac-1) activation: induced adhesion to HUVECs was inhibited by blocking mAbs anti-CD18 (70%-90%), anti-CD11a (50%-60%), or anti-CD11b (60%-70%). Adhesion to immobilized ligands of beta(2) integrins (intercellular adhesion molecule-1 [ICAM-1], fibrinogen, keyhole limpet hemocyanin) as well as to ICAM-1-transfected Chinese hamster ovary cells, but not to ligands of beta(1) integrins (VCAM-1, fibronectin, laminin, and collagen), was augmented. VCAM-1-Fc binding provoked the expression of the activation-dependent epitope CBRM1/5 of Mac-1 on leukocytes. Clustering of VLA-4 through dimeric VCAM-1-Fc was required for beta(2) integrin activation and induction of cell adhesion, whereas monovalent VCAM-1 or Fab fragments of anti-beta(1) integrin mAb were ineffective. Activation of beta(2) integrins by alpha(4)beta(1) integrin ligation (VCAM-1-Fc or anti-beta(1) mAb) required the presence of urokinase receptor (uPAR) on leukocytic cells, because the removal of uPAR from the cell surface by phosphatidylinositol-specific phospholipase C reduced cell adhesion to less than 40%. Adhesion was reconstituted when soluble recombinant uPAR was allowed to reassociate with the cells. Finally, VLA-4 engagement by VCAM-1-Fc or anti-beta(1) integrin mAb induced uPAR-dependent adhesion to immobilized vitronectin as well. These results elucidate a novel activation pathway of beta(2) integrin-dependent cell-to-cell adhesion that requires alpha(4)beta(1) integrin ligation for initiation and uPAR as activation transducer. (Blood. 2000;96:506-513)

The dual role of the urokinase receptor system in pericellular proteolysis and cell adhesion: implications for cardiovascular function.

Cell-cell and cell-matrix interactions are key events in morphogenetic processes during development and tissue remodelling. In the vascular system, overexpression of adhesion receptors such as integrins, protease (receptors) or dysregulation of adhesive interactions are directly related to the pathophysiology of cardiovascular diseases (atherosclerosis, restenosis, thrombosis) or angiogenesis-driven tumor progression. Protease cascades such as the plasminogen activation system exhibit a dual role in cell invasion by promoting pericellular proteolysis as well as by regulating cell adhesion and migration in a non-proteolytic fashion. In both these mechanisms, the urokinase receptor (uPAR) plays a central role and may become engaged in complexes with beta1-, beta2-, and beta3-integrins. This article will focus on the molecular and functional interactions between the uPAR system and vascular integrins and discuss implications for cardiovascular function.

Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo.

The urokinase receptor (CD87; uPAR) is found in close association with beta 2 integrins on leukocytes. We studied the functional consequence of this association for leukocyte adhesion and migration. In vivo, the beta 2 integrin-dependent recruitment of leukocytes to the inflamed peritoneum of uPAR-deficient mice was significantly reduced as compared with wild-type animals. In vitro, beta 2 integrin-mediated adhesion of leukocytes to endothelium was lost upon removal of uPAR from the leukocyte surface by phosphatidyl-inositol-specific phospholipase C. Leukocyte adhesion was reconstituted when soluble intact uPAR, but not a truncated form lacking the uPA-binding domain, was allowed to reassociate with the cell surface. uPAR ligation with a monoclonal antibody induced adhesion of monocytic cells and neutrophils to vascular endothelium by six- to eightfold, whereas ligation with inactivated uPA significantly reduced cell-to-cell adhesion irrespective of the beta 2 integrin-stimulating pathway. These data indicate that beta 2 integrin-mediated leukocyte-endothelial cell interactions and recruitment to inflamed areas require the presence of uPAR and define a new phenotype for uPAR-deficient mice. Moreover, uPAR ligation differentially modulates leukocyte adhesion to endothelium and provides novel targets for therapeutic strategies in inflammation-related vascular pathologies.

A comparison of the effects of alfentanil/droperidol or fentanyl/droperidol on intra-ocular pressure.

The influence of two intravenous sedative regimens on intra-ocular pressure was investigated in conjunction with retrobulbar local anaesthesia. Forty patients were allocated randomly to either group A (alfentanil and droperidol) or group F (fentanyl and droperidol). Measurements of intra-ocular pressure, arterial pressure and oxygen saturation were made before operation, after premedication, after intravenous sedation and after surgery. Paco2 was also measured before and after operation. Each sedation technique caused a similar reduction in intra-ocular pressure. There was less effect on Paco2 and oxygenation in group A.

Physostigmine in open-heart surgery. Reversal of hyoscine supplementation of morphine-oxygen-air-relaxant anaesthesia.

The use of physostigmine salicylate to reverse hyoscine supplementation of morphine-oxygen-air relaxant anaesthesia has been studied in twenty open-heart surgery patients and found to be both reliable and innocuous.