Parenteral anticoagulants in heart disease: Current status and perspectives (Section II). Position Paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease.

Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.

AIMS: Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS: CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION: EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.

Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha.

The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85alpha, p55alpha, and p50alpha impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. Pik3r1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the Pik3r1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-beta co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that Pik3r1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis.

Endocardite infectieuse: mise au point [Infective endocarditis: update]

The pathogenesis of infective endocarditis (IE) is being dissected at the molecular level, which should help redefine new preventive and therapeutic strategies against IE. In spite of improving health care, the incidence of IE has not decreased over the last decades. While classical predisposing conditions such as rheumatic heart disease were being eradicated, new features of IE have emerged. These include IE in intravenous drug users, IE in elderly patients with sclerotic valve disease, prosthetic valve IE and nosocomial IE. The epidemiology, pathogenesis, diagnosis, prevention and treatment of IE are being reviewed in this article.

Les infections endo-artérielles, complications redoutables des infections à salmonelles non typhi [Endarterial infections, redoubtable complications of non-typhi salmonella infections].

Three cases are reported of salmonella aortitis observed in three men aged 55, 60 and 48 years, the last of whom had a prosthetic aortic valve and ascending aorta. The microorganisms were S. typhi murium, S. paratyphi B, and S. wien. Despite antibiotic treatment two patients died of perforating aortitis. The third patient developed S. wien gastroenteritis a few days after surgical replacement of the aortic valve and the ascending aorta. Five years later he presented with several bacteremic episodes due to S. wien, which recurred despite several courses of cotrimoxazole treatment. He has now been asymptomatic for over one year under prolonged cotrimoxazole treatment. Since vascular infection may occur following non typhi salmonellosis in 5% of patients over 50, or who have underlying endothelial lesions, the question arises as to whether non typhi S. gastroenteritis should be treated with antibiotics in these high risk patients, in contrast to present recommendations.

Monitoring of noninvasive ventilation by built-in software of home bilevel ventilators: a bench study.

BACKGROUND: Current bilevel positive-pressure ventilators for home noninvasive ventilation (NIV) provide physicians with software that records items important for patient monitoring, such as compliance, tidal volume (Vt), and leaks. However, to our knowledge, the validity of this information has not yet been independently assessed. METHODS: Testing was done for seven home ventilators on a bench model adapted to simulate NIV and generate unintentional leaks (ie, other than of the mask exhalation valve). Five levels of leaks were simulated using a computer-driven solenoid valve (0-60 L/min) at different levels of inspiratory pressure (15 and 25 cm H(2)O) and at a fixed expiratory pressure (5 cm H(2)O), for a total of 10 conditions. Bench data were compared with results retrieved from ventilator software for leaks and Vt. RESULTS: For assessing leaks, three of the devices tested were highly reliable, with a small bias (0.3-0.9 L/min), narrow limits of agreement (LA), and high correlations (R(2), 0.993-0.997) when comparing ventilator software and bench results; conversely, for four ventilators, bias ranged from -6.0 L/min to -25.9 L/min, exceeding -10 L/min for two devices, with wide LA and lower correlations (R(2), 0.70-0.98). Bias for leaks increased markedly with the importance of leaks in three devices. Vt was underestimated by all devices, and bias (range, 66-236 mL) increased with higher insufflation pressures. Only two devices had a bias < 100 mL, with all testing conditions considered. CONCLUSIONS: Physicians monitoring patients who use home ventilation must be aware of differences in the estimation of leaks and Vt by ventilator software. Also, leaks are reported in different ways according to the device used.

Hématome des muscles ilio-psoas: rappel des éléments diagnostiques

Introduction: La survenue d'une hémorragie dans les muscles iliopsoasconstitue une pathologie grave, dont le diagnostic est souventtardif et grevé d'une morbidité importante. Sa présentation cliniquedoit être reconnue précocement, en particulier par les médecins depremier recours.Cas clinique: Un patient de 65 ans est admis aux urgences en raisonde douleurs invalidantes de la jambe droite, prédominant sur la faceantérieure de la cuisse. Les douleurs irradient dans le pli inguinal, leflanc, la région lombaire, ainsi que la hanche droite. Elles sont associéesà une parésie du quadriceps droit. Le patient a bénéficié en2006 d'un remplacement de valve aortique, avec implantation d'unevalve mécanique motivant une anticoagulation par acenocoumarol.Il présente par ailleurs une parésie sur le territoire du nerf sciatiquedroit, après fracture du bassin en 1970. Le diagnostic est évoqué auvu d'une antioagulation supra-thérapeutique (INR 5).Un CT-scan de l'abdomen confirmera un important hématome(11 x 7 cm) du muscle iliaque droit (fig. 1) qui sera drainé chirurgicalement,après réversion partielle de la crase, permettant une évolutionfavorable.Discussion: Les hématomes des muscles ilio-psoas surviennentclassiquement de manière spontanée. Les symptômes sont peu spécifiques,à type de douleurs diffuses abdominales, lombaires ou crurales,de paresthésies, de limitation fonctionnelle ou de chute isoléede l'hémoglobine (Hb). Les patients sous anticoagulants (héparine,acenocoumarol) ou présentant des troubles de la coagulation (hémophilie,thrombopathie, maladie de von Willebrand) sont particulièrementà risque. Les complications sont fréquentes: compressions dunerf fémoral (avec hypoesthésie, parésie du quadriceps ou abolitiondu réflexe rotulien), anémie, état de choc. Le traitement implique lacorrection des troubles de la coagulation, ainsi qu'un suivi clinique,radiologique et biologique (Hb) régulier. Le traitement conservateurest proposé lors d'hématome de petite taille, si le patient est stable etpeu symptomatique. Dans les autres cas, un drainage chirurgical parvoie ouverte ou par voie percutanée est recommandé. L'embolisationartérielle s'affiche comme une future option thérapeutique.Conclusions: Ce cas illustre les différents éléments cliniques etbiologiques qui orientent précocement vers le diagnostic d'hématomedes muscles ilio-psoas. Il devrait favoriser l'évocation d'une pathologierare, permettant de garantir un diagnostic précoce.

Connexin 43 expression in human hypertrophied heart due to pressure and volume overload.

Left ventricular hypertrophy (LVH) is due to pressure overload or mechanical stretch and is thought to be associated with remodeling of gap-junctions. We investigated whether the expression of connexin 43 (Cx43) is altered in humans in response to different degrees of LVH. The expression of Cx43 was analyzed by quantitative polymerase chain reaction, Western blot analysis and immunohistochemistry on left ventricular biopsies from patients undergoing aortic or mitral valve replacement. Three groups were analyzed: patients with aortic stenosis with severe LVH (n=9) versus only mild LVH (n=7), and patients with LVH caused by mitral regurgitation (n=5). Cx43 mRNA expression and protein expression were similar in the three groups studied. Furthermore, immunohistochemistry revealed no change in Cx43 distribution. We can conclude that when compared with mild LVH or with LVH due to volume overload, severe LVH due to chronic pressure overload is not accompanied by detectable changes of Cx43 expression or spatial distribution.

Infective endocarditis.

Infective endocarditis (IE) is lethal if not aggressively treated with antibiotics alone or in combination with surgery. The epidemiology of this condition has substantially changed over the past four decades, especially in industrialized countries. Once a disease that predominantly affected young adults with previously well-identified valve disease--mostly chronic rheumatic heart disease--IE now tends to affect older patients and new at-risk groups, including intravenous-drug users, patients with intracardiac devices, and patients exposed to healthcare-associated bacteremia. As a result, skin organisms (for example, Staphylococcus spp.) are now reported as the pathogen in these populations more often than oral streptococci, which still prevail in the community and in native-valve IE. Moreover, progress in molecular diagnostics has helped to improve the diagnosis of poorly cultivable pathogens, such as Bartonella spp. and Tropheryma whipplei, which are responsible for blood-culture-negative IE more often than expected. Epidemiological data indicate that IE mostly occurs independently of medico-surgical procedures, and that circumstantial antibiotic prophylaxis is likely to protect only a minute proportion of individuals at risk. Therefore, new strategies to prevent IE--including improvement of dental hygiene, decontamination of carriers of Staphylococcus aureus, vaccination, and, possibly, antiplatelet therapy--must be explored.

Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Development of fluid conduits in the auriferous shear zones of the Hutti Gold Mine, India: evidence for spatially and temporally heterogeneous fluid flow

The gold mineralization of the Hutti Mine is hosted by nine parallel, N - S trending, steeply dipping, 2 - 10 m wide shear zones, that transect Archaean amphibolites. The shear zones were formed after peak metamorphism during retrograde ductile D, shearing in the lower amphibolite facies. They were reactivated in the lower to mid greenschist facies by brittle-ductile D-3 shearing and intense quartz veining. The development of a S-2-S-3 crenulation cleavage facilitates the discrimination between the two deformation events and contemporaneous alteration and gold mineralization. Ductile D, shearing is associated with a pervasively developed distal chlorite - sed cite alteration assemblage in the outer parts of the shear zones and the proximal biotite-plagioclase alteration in the center of the shear zones. D3 is characterized by development of the inner chlorite-K-feldspar alteration, which forms a centimeter-scale alteration halo surrounding the laminated quartz veins and replaces earlier biotite along S-3. The average size of the laminated vein systems is 30-50 m along strike as well as down-dip and 2-6 m in width. Mass balance calculations suggest strong metasomatic changes for the proximal biotite-plagioclase alteration yielding mass and volume increase of ca. 16% and 12%, respectively. The calculated mass and volume changes of the distal chlorite-sericite alteration (ca. 11%, ca. 8%) are lower. The decrease in 6180 values of the whole rock from around 7.5 parts per thousand for the host rocks to 6-7 parts per thousand for the distal chlorite-sericite and the proximal biotite-plagioclase alteration and around 5 parts per thousand for the inner chlorite-K-feldspar alteration suggests hydrothermal alteration during two-stage deformation and fluid flow. The ductile D-2 deformation in the lower amphibolite facies has provided grain scale porosities by microfracturing. The pervasive, steady-state fluid flow resulted in a disseminated style of gold-sulfide mineralization and a penetrative alteration of the host rocks. Alternating ductile and brittle D3 deformation during lower to mid greenschist facies conditions followed the fault-valve process. Ductile creep in the shear zones resulted in a low permeability environment leading to fluid pressure build-up. Strongly episodic fluid advection and mass transfer was controlled by repeated seismic fracturing during the formation of laminated quartz(-gold) veins. The limitation of quartz veins to the extent of earlier shear zones indicate the importance of preexisting anisotropies for fault-valve action and economic gold mineralization. (C) 2003 Elsevier B.V. All rights reserved.

Obstructive pulmonary artery sarcoma.

A 68 year-old woman presented with increasing dyspnoea (NYHA II) and systolic murmur at auscultation. Echocardiography showed thickened pulmonary valve leaflets, a systolic prolapsing mass provoking severe pulmonary stenosis (peak systolic pulmonary pressure: 42 mmHg), no regurgitation, minimal right ventricular dilatation but normal ventricular function. CT scan showed a dense structure extending from the right ventricular outflow tract (RVOT) up to the pulmonary bifurcation infiltrating the pulmonary valve (PV).

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2.

The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling.

Fluid dynamics simulation of right ventricular outflow tract oversizing.

OBJECTIVES: Repair of the right ventricular outflow tract (RVOT) in paediatric cardiac surgery remains challenging due to the high reoperation rate. Intimal hyperplasia and consequent arteriosclerosis is one of the most important limitation factors for graft durability. Since local shear stress and pressure are predictive elements for intimal hyperplasia and wall degeneration, we sought to determine in an oversized 12-mm RVOT model, with computed fluid dynamics simulation, the local haemodynamical factors that may explain intimal hyperplasia. This was done with the aim of identifying the optimal degree of oversizing for a 12-mm native RVOT. METHODS: Twenty domestic pigs, with a weight of 24.6 ± 0.89 kg and a native RVOT diameter of 12 ± 1.7 mm, had valve conduits of 12, 16, 18 and 20 mm implanted. Pressure and flow were measured at 75, 100 and 125% of normal flow at RVOT at the pulmonary artery, pulmonary artery bifurcation and at the left and right pulmonary arteries. Three-dimensional computed fluid dynamics (CFD) simulation in all four geometries in all flow modalities was performed. Local shear stress and pressure conditions were investigated. RESULTS: Corresponding to 75, 100 and 125% of steady-state flow, three inlet velocity profiles were obtained, 0.2, 0.29 and 0.36 m/s, respectively. At inflow velocity profiles, low shear stress areas, ranged from 0 to 2 Pa, combined with high-pressure areas ranging from 11.5 to 12.1 mmHg that were found at distal anastomosis, at bifurcation and at the ostia of the left and right pulmonary arteries in all geometries. CONCLUSIONS: In all three oversized geometries, the local reparation of shear stress and pressure in the 16-mm model showed a similar local profile as in the native 12 mm RVOT. According to these findings, we suggest oversizing the natural 12-mm RVOT by not more than 4 mm. The elements responsible for wall degeneration and intimal hyperplasia remain very similar to the conditions present in native RVOT.