Andrew Mavor MD FRCS(Ed)

• Consultant vascular surgeon
• Leeds General Infirmary, Leeds
• Honorary senior lecturer, University of Leeds
• Examiner for RCS Edinburgh, UK

The nonspe arteriograms are then obtained at reduced contrast inj ection rates and quantities virus living or not generic 500mg ciplox. The pulmonary artery with the largest central embolus is cannulated antibiotic resistant uti in pregnancy cheap generic ciplox canada, and a 7F-long sheath is placed wire finished antibiotics for uti still have symptoms order 500 mg ciplox with mastercard. Catheter-directed mechanical thrombofragmentation over a heavy-duty guide wire or an Amplatz superstiff guide under fluoroscopy to assess pulmonary artery blood flow and the severity of pulmonary emboli antibiotic 5440 buy discount ciplox on-line. Right and left pulmonary cific nature of these findings may substantially delay diag nosis antibiotic ointment for babies ciplox 500 mg discount. The chest radiograph usually reveals right ventricular enlargement and enlarged main pulmonary arteries infection 5 metal militia purchase 500 mg ciplox with mastercard. Arte rial blood gases often reveal resting hypoxemia with a wid ened A-a gradient. Echocardiography documents pulmonary hypertension and right ventricular dilation and dysfunction. The procedure involves a median sternotomy pressure, may identify patients at risk for persistent pulmo nary hypertension and poor outcome following pulmonary thromboendarterectomy. Angiography reveals nonspecific dilatation of the proxi mal pulmonary arteries with smooth, rapid tapering of distal arteries may also be seen. Right heart catheterization is the gold standard for establishing the presence of pulmonary Echocardiography usually first documents the presence of pulmonary hypertension in patients with unexplained dys pnea or fatigue. In the presence of pulmonary hypertension Most patients have a high-probability ventilation perfusion scan. Acute drug challenge is also recommended in patients with end-stage congestive heart failure to prove that high pulmonary vascular resistance is not fixed and to ensure eligibility for heart transplantation. Polycythemia and reduced arterial P0 are manifestations of an extracardiac right-to 2 left shunt. The dose is up-titrated until systemic effects (headache, flushing, or nausea) occur. In contrast to epoprostenol or adenosine, nitric oxide usually a complex branching mass, supplied by one to three subsegmental arteries, all arising from the same segmental has no inotropic properties and does not increase cardiac out put. When intervention is planned, ographic procedure must be meticulously followed to avoid air embolism, catheter thrombosis, or embolism of occlusion St. With the potential for direct systemic emboli, extreme caution must be exercised and angi devices. Pulmonary blood ing pulmonary artery banding after systemic to pulmonary artery shunts such as Blalock- Taussig, Waterston- Cooley, or Glenn anastomosis. Stenosis may also be secondary to rubella, chronic infections (such as histoplasmosis), or infestations (such as schistosomiasis). Angioplasty and stent placement for treatment of pulmonary artery stenoses have been used primarily for treatment of congenital stenoses. Pulmonary vein stenosis is increasingly seen in patients who undergo radiofrequency ablation of the pulmonary venous ostia for treatment of atrial fibrillation. Balloon angioplasty with or without stent placement has been used successfully to treat symptomatic patients. O ther infectious causes of pul monary artery aneurysms include syphilis and septic emboli. Most aneurysms occur centrally, Pulmonary artery aneurysms may appear as a perihilar of bronchial and nonbronchial systemic collateral arteries. The etiology includes lung transplantation, lobectomy, lung resection, Swan-Ganz catheterization, and expandable bronchial stent placement 92 In patients with massive hemoptysis, fiberoptic bronchoscopy should be per formed to determine the causes so that appropriate endovas airway must be protected before specific interventions can be initiated. When a pulmonary artery-bronchial fistula is sus pected, a Fogarty balloon-tipped catheter should be inflated ment of a l 2F sheath in the femoral vein, a pulmonary artery to occlude the bleeding bronchus. At the same time, the is not observed, a repeat angiogram is performed after defla tion of the balloon. It typically is seen in the main pulmonary artery in relation important to evaluate the venous phase for any pulmonar venous involvement. Because no direct access to the pulmonary vein is available, percu taneous direct temic arterial inj e ction in the presence of systemic artery pulmonary arteries. Transesophageal the pulmonary arteries and veins as they traverse the mediastinu m. P ercuta neous retrieval using a nitinol snare (Amplatz G ooseneck fied the approach to foreign body removal. Balloons are well suited to engage lost stents and either to redeploy the stent in a safer location or to remove it. Pulmonary angiography with delayed film ing is useful for diagnosis and quantification of the left to-right shunt. Transfemoral venous cath eterization through inferior vena caval filters: results in seven cases. Transfemoral selective bilat eral pulmonary arteriography with a pulmonary artery-seeking catheter. Pulmonary angiography with iopamidol: patient comfort, image quality, and hemodynamics. Catheter replacement of the needle in percutaneous arte riography: a new technique. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Activation of platelets by low-osmolar contrast media: differential effects of ionic and nonionic agents. Transbrachial selective pulmonary angiography using a new 4 Fr curved pigtail catheter and hydrophilic-coated guidewire. Pulmonary embolism: com parison of cut-film and digital pulmonary angiography Radiology 1998;207: 139-145. Possible pulmonary embolus: evaluation with digital subtraction versus cut-film angiography prospective study in 80 patients. Clinical follow-up of patients after a negative digital subtraction pulmonary arteriogram in the evaluation of pulmonary embolism. Hemodynamic effects of nonionic contrast bolus inj ection and oxygen inhalation dur ing pulmonary angiography in patients with chronic major vessel thromboembolic pulmonary hypertension. Right ventricular enlarge ment on chest computed tomography: prognostic role in acute pul monary embolism. Comparison of contrast-enhanced magnetic resonance angiography and conven tional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 3 6 7 patients. Quantitative plasma D - dimer levels among patients undergoing pulmo nary angiography for suspected pulmonary embolism. N ormal D-dimer levels in emergency department patients suspected of acute pulmonary embolism. The accuracy of the enzyme linked immunosorbent assay D-dimer test in the diagnosis of pulmo nary embolism: a metaanalysis. A prospective evaluation of a quantitative D-dimer assay in the evaluation of acute pulmonary embolims. Anatomic distri bution of pulmonary emboli at pulmonary angiography: implica tions for cross-sectional imaging. The role of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism. The clini cal course of patients with suspected pulmonary embolism and a negative pulmonary arteriogram. Continuing risk of thromboem boli among patients with normal pulmonary angiograms. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Pulmonary arteriovenous malfor mations: diagnosis and transcatheter embolotherapy. Plain radio graphi c, of nuclear medicine pulmonary and angiographic observations hepatogenic angiodysplasia. Importance of car diac troponins I and T in risk stratification of patients with acute pulmonary embolism. Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter. Massive pulmonary embolism: preliminary results in treatment with the Amplatz thrombectomy device. Implantation and inter mediate-term follow-up of stents in congenital heart disease. Transcatheter angioplasty for acquired pulmonary vein stenosis after radiofrequency ablation. Peripheral pulmonary arte rial pseudoaneurysms: therapeutic implications of endovas cular treatment and angiographic classifications. Balloon pulmonary angioplasty for treatment of chronic thrombo embolic pulmonary hypertension. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thrombo embolic pulmonary 80. Pulmonary venous aneurysm presenting as a mediastinal mass in ischemic cardiomyopathy. Severe mitral regurgitation after valve replacement as cause of pulmonary venous aneurysm. Although specialists in vascular medicine and vascular surgery have long recognized that peripheral of patients annually in the United States. Historically, most tional procedures, and safe and reliable methods for continued surveillance. An evaluation of cross-sectional data sets, often referred to as "raw data, " permits a unique and highly detailed perspective angiographic evaluation using dedicated workstations to pro duce images in proj ections. Enhanced imaging tech niques now allow high-resolution single-breathhold images of the chest and great vessels without the need for gating, and techniques such as time resolved imaging of contrast kinetics sequences and Fourier transformation techniques are beyond the scope of this chapter. To produce this effect, thresholding arterial transit times, poor peripheral intravenous access, or marked asymmetry in limb flow, inadequate opacifica tion and image degradation may occur. As a result, a densely calcified and highly limitations, predominantly due to its dependency on contrast resolution between opacified vessels and the surrounding tissue. N ewer reconstruction techniques have been developed to overcome the problem associated with evaluating calci fied vessels. These principles are summarized in the recently updated consensus level of complexity and sophistication and, at this writing, remains the gold standard for diagnosis of arterial disease. General considerations include techniques of arterial access, radiographic equipment, catheter design and use, anticoagu conference guidelines regarding the clinical competency required for the diagnosis and management of peripheral vas cular diseases. Deciding on the appropriate site of access for peripheral arte complication-free procedure cannot be overstated, particu present in diseased arteries, can also aid as a fluoroscopic target. Ultrasound guidance, and road mapping of a contrast aorta from the contralateral groin, may also be helpful. Although many operators use crossover techniques inguinal ligament), removal of the needle and repuncture is recommended. Arterial calcification, which is frequently inj ection performed via a catheter positioned in the distal duration of the procedure. The most favorable site of access is determined based on the clinical history, physical exami nation, and noninvasive studies. Antegrade access is considered more challenging tech nically and limits angiography to the ipsilateral leg, but it offers a more stable platform for intervention. For retrograde femoral access, required, as compared with the standard 7 em needle used for retrograde access. A 9 em needle is frequently puncture should be performed under fluoroscopic guidance aiming for the mid or upper portion of the femoral head. This rare but devastating complica sion, renal failure, stroke, or potential death (see Chapter 4). Although there are no proven therapies effective in the man tion of arteriography may lead to livedo reticularis, hyperten diseased peripheral circulation to reduce the chance of embo agement of this dreadful complication, prostanoids. The wires that we recommend include a Bentson wire (with a 1 5 em floppy atraumatic tip), a Wholey wire (which provides a gentle steerable tip) or an angled Glidewire (which gives easy passage into the femoral circulation but must be used with care as it may track subintimally or be skeletonized from prior surgery, the use of nitinol core wires can be useful to prevent kinking. We recommend use of a 5F sheath until the site of arteriotomy and procedural requirement have been by the sharp edge of the access needle). Further postprocessing features include contrast inversion (changing white arterial structures to appear black), magnification, pixel shifting, picture integration (landmarking), contour enhancement, image stacking, image. This technique is used for selective cath and three-dimensional reconstruction of the subtracted confirmed. Anticoagulation agent should be administered once the correct position of the access point has been con firmed and if intervention is anticipated; anticoagulation is not routinely used in purely diagnostic angiography. Extra practice to consider reversing anticoagulation to facilitate care should be taken to remove the antegrade sheath promptly following the procedure to minimize complications. It is our manipulating catheters and guidewires in the severely immediate sheath removal in the catheterization laboratory, although the availability of closure devices has reduced the need to reverse anticoagulation. Although it is not used in cardiac work (where cardiac motion precludes acquiring a suitable the catheter is to be moved).

Furthermore antibiotic alternatives buy 500mg ciplox with amex, in the concept lies a possibility to alter a severe phenotype to a less diseased child infection in the blood buy ciplox discount. If this means that a fetus with a lethal condition will survive in a difficult condition is indeed a very problematic prospect virus free games buy ciplox 500mg line. Thus antibiotics after root canal ciplox 500mg without a prescription, considering the complexity of these issues how antibiotics for acne work buy cheap ciplox 500mg, there is an obvious need for a multidisciplinary approach and a cautious attitude virus zone ciplox 500mg with mastercard. Prenatal T-cell reconstitution after in utero transplantation with fetal liver cells in a patient with X-linked severe combined immunodeficiency. In utero transfer of adult bone marrow cells into recipients with severe combined immunodeficiency disorder yields lymphoid progeny with T- and B-cell functional capabilities. Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies. Clinical application of intrauterine bone marrow transplantation for treatment of genetic diseases-feasibility studies. In utero haematopoietic stem cell transplantation: current perspectives and future potential. Fetal hematopoietic stem cell transplantation: a challenge for the twenty-first century. In utero stem cell transplantation and gene therapy: rationale, history, and recent advances toward clinical application. In utero stem cell transplantation and gene therapy: recent progress and the potential for clinical application. Monoclonal derivation of mouse myeloid and lymphoid lineages from totipotent hematopoietic stem cells experimentally engrafted in fetal hosts. Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients. Development of adult bone marrow stem cells in H-2compatible and -incompatible mouse fetuses. Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. The maternal immune response inhibits the success of in utero hematopoietic cell transplantation. In utero bone marrow transplantation induces donorspecific tolerance by a combination of clonal deletion and clonal anergy. In utero transplantation of hematopoietic stem cells in sheep: the role of T cells in engraftment and graft-versus-host disease. Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates. On the feasibility of inducing tolerance in man: a study in the cynomolgus monkey. In utero bone marrow transplantation of fetal baboons with mismatched adult baboon marrow. In utero hematopoietic stem cell transplantation in nonhuman primates: the role of T cells. Enzyme replacement therapy-an experiment of nature in a chimeric mannosidosis calf. Equal distribution of congenital blood cell chimerism in dizygotic triplets after in-vitro fertilization. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with (111)indium radiolabeling. The dynamic in vivo distribution of bone marrowderived mesenchymal stem cells after infusion. The fate of mesenchymal stem cells transplanted into immunocompetent neonatal mice: implications for skeletal gene therapy via stem cells. Widespread distribution and muscle differentiation of human fetal mesenchymal stem cells after intrauterine transplantation in dystrophic mdx mouse. Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Identification of mesenchymal stem/ progenitor cells in human first- trimester fetal blood, liver, and bone marrow. Mesenchymal progenitor cells localize within hematopoietic sites throughout ontogeny. Allogenic fetal liver cells have a distinct competitive engraftment advantage over adult bone marrow cells when infused into fetal as compared with adult severe combined immunodeficient recipients. Mortality and causes of death in patients with osteogenesis imperfecta: a register-based nationwide cohort study. Fracture rates and fracture sites in patients with osteogenesis imperfecta: a nationwide register-based cohort study. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. The immunomodulatory potential of mesenchymal stromal cells: a story of a regulatory network. Superior osteogenic capacity for bone tissue engineering of fetal compared with perinatal and adult mesenchymal stem cells. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells. Comparative osteogenic transcription profiling of various fetal and adult mesenchymal stem cell sources. Differentiation of human fetal mesenchymal stem cells into cells with an oligodendrocyte phenotype. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta. Potential of human fetal chorionic stem cells for the treatment of osteogenesis imperfecta. Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Procedure-related complications and perinatal outcome after intrauterine transfusions in red cell alloimmunization in Stockholm. The impact of single gene and chromosomal disorders on hospital admissions of children and adolescents: a population-based study. Cost analysis of managing paediatric femoral shaft fractures: flexible intramedullary nailing versus nonoperative management. Minimally invasive ultrasound-guided injection techniques can be used to target gene therapy to fetal organs in animal models. Observed risks of fetal gene therapy include insertional mutagenesis, germline gene transfer, vector toxicity, the fetal and maternal immune response to the vector, and maternal and fetal morbidity and mortality. Currently, direct fetal gene therapy and in utero transplantation of gene-corrected fetal stem cells remains at the experimental stage. Vectors are the vehicles that are used to carry the genetic material into the cell. The genetic material that is transferred by this type of genetic engineering is called a transgene, and the introduction of the transgene has the potential to change the phenotype of a patient. The transgene contains (i) a promoter, which is a regulatory sequence that will determine where and when the transgene is active. In the cell, the transgene is expressed producing a transgenic protein that has the therapeutic effect. Somatic gene therapy treats an individual patient by insertion of genes into non germline cells that are either outside the body (ex vivo). Gene therapy can even be given to the mother when maternal pathology affects the fetus in utero. From the earliest days of gene therapy, however, correcting the germline was considered to be neither scientifically nor medically justifiable, technically unsafe and unpredictable and therefore ethically unacceptable. These include difficulty targeting the appropriate organ, a robust immune response to the therapy in adults and low-level expression of the therapeutic protein. In some diseases, gene therapy may be most effective when it is given early in neonatal life. When congenital disease pathology occurs during fetal development, then treating the fetus may be the best solution. Preclinical studies in animal models in the last 18 years have shown that fetal gene therapy can cure severe genetic disease. More recently, structural anomalies in fetuses have been prevented using a gene therapy approach. This gives couples time to 560 the Potential Advantages and Disadvantages of Fetal Gene Therapy the advantages of fetal gene therapy over postnatal treatment are summarised in Table 46. Production of clinical grade vector is time consuming and expensive, and the small size of the fetus could lead to increased vector biodistribution at the same vector dose as an adult. The vector can be directly applied to the fetus or the mother by ultrasound guided injection, called somatic gene therapy. Alternatively, stem cells can be collected from fetal fluid by ultrasound-guided sampling, gene corrected in the laboratory by incubation with the gene therapy vector and then reintroduced back into the fetus by ultrasound guided injection. Some individuals have preexisting antibodies to the viral vector that will prevent long-term expression of the transgenic protein, limiting therapeutic efficacy and preventing repeated vector administration. For human gestation, transgenic protein expression will need to last at least 6 months if the vector is given early in pregnancy, which limits the types of viral vectors that can be applied. Proof-of-principle studies have shown long-term expression of proteins at therapeutic levels and induction of immune tolerance12 in both small13 and large animals14,15 and cured congenital disease in some animal models. Vectors for Fetal Gene Transfer An ideal vector for prenatal gene therapy is one that can produce long-term regulated and therapeutic expression of the transferred gene through the use of a single and efficient gene delivery method and is safe to the mother and fetus, thus allowing incorporation into clinical practice. For example, a vector carrying the -globin gene should deliver and express the gene only to erythroid specific cells and lineages. Pseudotyping, for example, involves changing the virus capsid (outer covering) for one of a different serotype or of a completely different virus, thus altering its ability to infect particular cell types or organs. These can be derived from the genomes of mammals, viruses or other organisms and can even be manipulated to allow regulatable gene expression if required. This ensures that daughter cells contain the viral genetic material after cell division. Many replication-deficient lentiviruses are based on the immunodeficiency virus, and there is the theoretical possibility of reversion to the wild type. In third- and fourth-generation lentivirus vectors, however, the risk for in vivo generation of replication competent viruses is reduced by removal of the tat gene. Modification of virus elements, such as mutating the integrase in lentiviral vectors, renders it incapable of integrating and greatly reduces the risk for insertional mutagenesis. For more detailed information on vectors relevant to fetal gene therapy, the authors refer readers to other references. Reports of successful applications to genomic targets are appearing at an accelerating rate. Selecting the Right Disease for Fetal Gene Therapy As with any new therapeutic modality, the risks of fetal gene therapy are not well characterised. Careful thought must be given to decide on the right disease to select for a first-in-woman trial. Low level integration into Risk for hepatocellular active genes so theoretical cancer. Androgens increase gene transfer (transduction level higher in males>females) Potential for insertional Risk for germ-line transmission mutagenesis. There should be no effective postnatal therapy, or there is a poor outcome using available postnatal therapies. The treatment should correct all serious abnormalities that are associated with the disease. There should be an animal model that recapitulates the human disease or disorder for testing of in utero gene transfer. Some of the diseases that may be suitable for fetal treatment are listed in Table 46. Progress in the treatment of a group of inherited conditions, the lysosomal storage disorders, is discussed in detail here to illustrate recent progress. The lysosomal storage diseases are inherited deficiencies of lysosomal enzymes that lead to intracellular substrate accumulation. The treated animals did not develop cardiac disease or corneal clouding, and skeletal, cartilage and synovial disease was ameliorated. Injection of adenovirus into the cerebral ventricles of fetal mice led to widespread and long-term gene expression throughout the brain and the spinal cord. In contrast, ultrasound-guided access to the human fetal circulation is commonly used for fetal blood sampling and transfusions in clinical practice, with minimal fetal loss rate or complication.

A antimicrobial copper products buy ciplox 500mg cheap, Wrapping of a Schwann cell membrane around a large axon to form the myelin sheath of the myelinated nerve fiber antibiotic resistance lancet order ciplox american express. B dosage of antibiotics for sinus infection cheap ciplox 500mg otc, Partial wrapping of the membrane and cytoplasm of a Schwann cell around multiple unmyelinated nerve fibers (shown in cross section) infection mouth best purchase for ciplox. Second effective antibiotics for sinus infection generic ciplox 500mg mastercard, saltatory conduction conserves energy for the axon because only the nodes depolarize virus evolution discount ciplox 500 mg visa, allowing perhaps 100 times less loss of ions than would otherwise be necessary, and therefore requiring much less energy expenditure for re-establishing the sodium and potassium concentration differences across the membrane after a series of nerve impulses. The excellent insulation afforded by the myelin membrane and the 50-fold decrease in membrane capacitance also allow repolarization to occur with little transfer of ions. The velocity action potentials: mechanical pressure to excite sensory nerve endings in the skin, chemical neurotransmitters to transmit signals from one neuron to the next in the brain, and electrical current to transmit signals between successive muscle cells in the heart and intestine. The usual means for exciting a nerve or of action potential conduction in nerve fibers varies from as little as 0. When electricity is applied in this manner, the excitable membrane becomes stimulated at the negative electrode. Remember that the action potential is initiated by the opening of voltage-gated sodium channels. Furthermore, these channels are opened by a decrease in the normal resting electrical voltage across the membrane-that is, negative current from the electrode decreases the voltage on the outside of the membrane to a negative value nearer to the voltage of the negative potential inside the fiber. This effect decreases the electrical voltage across the membrane and allows the sodium channels to open, resulting in an action potential. Conversely, at the positive electrode, the injection of positive charges on the outside of the nerve membrane heightens the voltage difference across the membrane, rather than lessening it. This effect causes a state of hyperpolarization, which actually decreases the excitability of the fiber rather than causing an action potential. This automatic regenerative opening can result from mechanical disturbance of the membrane, chemical effects on the membrane, or passage of electricity through the membrane. However, when the voltage of the stimulus is increased, there comes a point at which excitation does take place. A weak stimulus at point A causes the membrane potential to change from -70 to -65 millivolts, but this change is not sufficient for the automatic regenerative processes of the action potential to develop. The stimulus does, however, disturb the membrane potential locally for as long as 1 millisecond or more after both of these weak stimuli. These local potential changes are called acute local potentials and, when they fail to elicit an action potential, they are called acute subthreshold potentials. Now, the local potential has barely reached the threshold level required to elicit an action potential, but this occurs only after a short "latent period. Thus, this figure shows that even a weak stimulus causes a local potential change at the membrane, but the intensity of the local potential must rise to a threshold level before the action potential is set off. Then, within another small fraction of a second, the inactivation gates of the channels open, and a new action potential can be initiated. The period during which a second action potential cannot be elicited, even with a strong stimulus, is called the absolute refractory period. Therefore, one can readily calculate that such a fiber can transmit a maximum of about 2500 impulses per second. Inhibition of Excitability-Stabilizers and Local Anesthetics In contrast to the factors that increase nerve excitability, membrane-stabilizing factors can decrease excitability. For example, a high extracellular fluid calcium ion concentration decreases membrane permeability to sodium ions and simultaneously reduces excitability. Among the most important stabilizers are the many substances used clinically as local anesthetics, including procaine and tetracaine. Most of these agents act directly on the activation gates of the sodium channels, making it much more difficult for these gates to open and thereby reducing membrane excitability. When excitability has been reduced so low that the ratio of action potential strength to excitability threshold (called the safety factor) is reduced below 1. The reason for this restriction is that shortly after the action potential is initiated, the sodium channels (or calcium channels, or both) become inactivated, and no amount of excitatory signal applied to these channels at this point will open the inactivation gates. The only condition that will allow them to reopen is for the membrane potential to return to or near the original 40 20 Millivolts 0 20 40 60 80 0 A 1 B C 2 3 Milliseconds D 4 Acute subthreshold potentials Threshold Bibliography Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 5th ed. Note the development of acute subthreshold potentials when the stimuli are below the threshold value required for eliciting an action potential. Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system Nat Rev Neurosci. Voltage-gated calcium channels: key players in sensory coding in the retina and the inner ear. In this articler, we mainly consider skeletal muscle function; the specialized functions of smooth muscle are discussed in Chapter 8, and cardiac muscle is discussed in Chapter 9. The light bands contain only actin filaments and are called I bands because they are isotropic to polarized light. The dark bands contain myosin filaments, as well as the ends of the actin filaments, where they overlap the myosin, and are called A bands because they are anisotropic to polarized light. It is the interaction between these cross-bridges and the actin filaments that causes contraction (Video 6-1). From this disk, these filaments extend in both directions to interdigitate with the myosin filaments. The Z disk, which is composed of filamentous proteins different from the actin and myosin filaments, passes crosswise across the myofibril and also crosswise from myofibril to myofibril, attaching the myofibrils to one another all the way across the muscle fiber. Therefore, the entire muscle fiber has light and dark bands, as do the individual myofibrils. The portion of the myofibril (or of the whole muscle fiber) that lies between two successive Z disks is called a sarcomere. At this length, the actin filaments completely overlap the myosin filaments, and the tips of the actin filaments are just beginning to overlap one another. As discussed later, at this length, the muscle is capable of generating its greatest force of contraction. Except for about 2% of the fibers, each fiber is usually innervated by only one nerve ending, located near the middle of the fiber. The sarcolemma consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils. At each end of the muscle fiber, this surface layer of the sarcolemma fuses with a tendon fiber. The tendon fibers, in turn, collect into bundles to form the muscle tendons that then connect the muscles to the bones. Each titin molecule has a molecular weight of about 3 million, which makes it one of the largest protein molecules in the body. Also shown in cross section are T tubules (arrows) that lead to the exterior of the fiber membrane and are important for conducting the electrical signal into the center of the muscle fiber. Part of the titin molecule is closely associated with the myosin thick filament, whereas the rest of the molecule is springy and changes length as the sarcomere contracts and relaxes. This reticulum has a special organization that is extremely important in regulating calcium storage, release, reuptake and therefore muscle contraction, as discussed in Chapter 7. The rapidly contracting types of muscle fibers have especially extensive sarcoplasmic reticula. At each ending, the nerve secretes a small amount of the neurotransmitter acetylcholine. Acetylcholine acts on a local area of the muscle fiber membrane to open acetylcholine-gated cation channels through protein molecules floating in the membrane. The opening of acetylcholine-gated channels allows large quantities of sodium ions to diffuse to the interior of the muscle fiber membrane. This action causes a local depolarization that in turn leads to the opening of voltage-gated sodium channels, which initiates an action potential at the membrane. The action potential travels along the muscle fiber membrane in the same way that action potentials travel along nerve fiber membranes. The action potential depolarizes the muscle membrane, and much of the action potential electricity flows through the center of the muscle fiber. Here it causes the sarcoplasmic reticulum to release large quantities of calcium ions that have been stored within this reticulum. One end of the titin molecule is elastic and is attached to the Z disk, acting as a spring and changing length as the sarcomere contracts and relaxes. The titin molecule may also act as a template for the initial formation of portions of the contractile filaments of the sarcomere, especially the myosin filaments. The spaces between the myofibrils are filled with intracellular fluid called sarcoplasm, containing large quantities of potassium, magnesium, and phosphate, plus multiple protein enzymes. Also present are tremendous numbers of mitochondria that lie parallel to the myofibrils. The calcium ions initiate attractive forces between the actin and myosin filaments, causing them to slide alongside each other, which is the contractile process. After a fraction of a second, the calcium ions are pumped back into the sarcoplasmic reticulum by a Ca2+ membrane pump and remain stored in the reticulum until a new muscle action potential comes along; this removal of calcium ions from the myofibrils causes the muscle contraction to cease. Also shown are thousands of myosin cross-bridges and interaction between the heads of the crossbridges with adjacent actin filaments. Molecular Characteristics of the Contractile Filaments Myosin Filaments Are Composed of Multiple Myosin Molecules. It shows the relaxed state of a sarcomere (top) and the contracted state (bottom). In the relaxed state, the ends of the actin filaments extending from two successive Z disks barely overlap one another. Conversely, in the contracted state, these actin filaments have been pulled inward among the myosin filaments, so their ends overlap one another to their maximum extent. Also, the Z disks have been pulled by the actin filaments up to the ends of the myosin filaments. This action is caused by forces generated by interaction of the cross-bridges from the myosin filaments with the actin filaments. Under resting conditions, these forces are inactive, but when an action potential travels along the muscle fiber, this causes the sarcoplasmic reticulum to release large quantities of calcium ions that rapidly surround the myofibrils. The two heavy chains wrap spirally around each other to form a double helix, which is called the tail of the myosin molecule. One end of each of these chains is folded bilaterally into a globular polypeptide structure called a myosin head. These light chains help control the function of the head during muscle contraction. Also, part of the body Chapter 6 Contraction of Skeletal Muscle Active sites Troponin complex F-actin Tropomyosin Each actin filament is about 1 micrometer long. Attached to one end of each tropomyosin molecule is a troponin complex that initiates contraction. The actin filament also con- of each myosin molecule hangs to the side along with the head, thus providing an arm that extends the head outward from the body, as shown in the figure. Each cross-bridge is flexible at two points called hinges-one where the arm leaves the body of the myosin filament and the other where the head attaches to the arm. The hinged arms allow the heads either to be extended far outward from the body of the myosin filament or brought close to the body. The hinged heads, in turn, participate in the contraction process, as discussed in the following sections. Note, however, that there are no cross-bridge heads in the center of the myosin filament for a distance of about 0. Now, to complete the picture, the myosin filament is twisted so that each successive pair of cross-bridges is axially displaced from the previous pair by 120 degrees. This twisting ensures that the cross-bridges extend in all directions around the filament. Another feature of the myosin head that is es- tains another protein, tropomyosin. Each molecule of tropomyosin has a molecular weight of 70,000 and a length of 40 nanometers. In the resting state, the tropomyosin molecules lie on top of the active sites of the actin strands so that attraction cannot occur between the actin and myosin filaments to cause contraction. Contraction occurs only when an appropriate signal causes a conformation change in tropomyosin that "uncovers" active sites on the actin molecule and initiates contraction, as explained later. Attached intermittently along the sides of the tropomyosin molecules are additional protein molecules called troponin. These protein molecules are actually complexes of three loosely bound protein subunits, each of which plays a specific role in controlling muscle contraction. One of the subunits (troponin I) has a strong affinity for actin, another (troponin T) for tropomyosin, and a third (troponin C) for calcium ions. The strong affinity of the troponin for calcium ions is believed to initiate the contraction process, as explained in the next section. Interaction of One Myosin Filament, Two Actin Filaments, and Calcium Ions to Cause Contraction Inhibition of the Actin Filament by the TroponinTropomyosin Complex. Each strand of the double F-actin helix is composed of polymerized G-actin molecules, each having a molecular weight of about 42,000. The active sites on the two F-actin strands of the double helix are staggered, giving one active site on the overall actin filament about every 2. Then, if the troponin-tropomyosin complex is added to the actin filament, the binding between myosin and actin does not take place. Therefore, it is believed that the active sites on the normal actin filament of the relaxed muscle are inhibited or physically covered by the troponin-tropomyosin complex. Consequently, the sites cannot attach to the heads of the myosin filaments to cause contraction. Before contraction can take place, the inhibitory effect of the troponin-tropomyosin complex must itself be inhibited. In the presence of large amounts of calcium ions, the inhibitory effect of the troponin- tropomyosin on the actin filaments is itself inhibited. The mechanism of this inhibition is not known, but one suggestion has been presented.

On physical examination her blood pressure was 1 0 5/60 mmHg with a heart rate of 89 bpm infection knee pain discount 500 mg ciplox mastercard. On cardiac auscultation bacterial 16s rrna universal primers purchase ciplox with a mastercard, she had a normal 5 and a physio 1 logically split 5 with a loud pulmonic component virus action sports buy ciplox 500mg otc. She was treated with an oral endothelin receptor antagonist and currently has dyspnea only with severe exertion bacteria que causa la gastritis order ciplox cheap. Six months later the patient was admit ted with worsening lower extremity edema antibiotics for acne amoxicillin quality ciplox 500mg, hypotension antimicrobial quiz questions purchase discount ciplox, and hyponatremia. The patient elected to undergo initiation of treprostinil via subcutaneous infusion. Lung transplantation evaluation and combination therapy with an oral endothelin receptor antagonist, along with dual forms of birth control, were initiated. She experienced significant improvement in her symptoms and 6-minute hall-walks over the next 2 years, but then discontinued the endothelin receptor antagonist ow ing to hepatotoxicity. The patient was listed for lung transplantation and referred for atrial septostomy. Inflations were then performed across the interatrial septum with a 1 0 mm X 20 mm Opta balloon that was inflated to a maximum of 5 atm. The systemic 0 saturation was 92% on 2 liters of oxygen 2 nasal cannula and 87% on room air. A lung transplant donor was identified, and she underwent success ful double lung transplantation with closure of the atrial sep tal defect. Clinical outcome may improve with pulmonary thromboendarterectomy in combination with placement of a vena cava filter and indefinite-duration anticoagulation. The most common symptoms and signs are nonspecific: dyspnea, chest pain, tachypnea, and tachycardia. Usually, pulmonary embolism patients with pleuritic pain or hemoptysis have anatomically small emboli near the periphery of the lung, where nerve innervation is the maximum and where pulmonary infarction is most likely to occur owing to poor collateral circulation. Furthermore, the chest radiograph can help identify patients with other diseases such as lobar pneumonia or pneumothorax that can mimic pulmonary embolism. The electrocardiogram helps to exclude acute myocardial infarction and to identify electrocardiographic manifestations of right-heart strain 25-27 the differential diagnosis of new right heart strain includes acute pulmonary embolism, acute asthma, or exacerbation of chronic bronchitis in patients with chronic obstructive pulmonary disease. Unfortunately, the time-honored screening test of abnormal room air arterial blood gases is not helpful in tri aging patients suspected of pulmonary embolism. D-dimer levels remain elevated in patients for at least 1 week postoperatively and will also be abnormally high in patients with myocardial infarction, sepsis, or almost any other systemic illness. The V-Q scan is most useful if it is clearly normal or if it demonstrates a pattern suggestive of a high probability for pulmonary embolism. Risk Stratification Contemporary risk stratification focuses on early detection of those patients who are at increased risk for adverse clinical events while the systemic arterial pressure is preserved, prior to the development of cardiogenic shock. Clinical signs of right ventricular dysfunction include distended jugular veins, an accentuated pulmonic heart sound, a right ventricular heave, or a tricuspid regurgitation murmur. Myocardial ischemia and microinfarction owing to alterations in oxygen supply and demand of the failing right ventricle probably play a maj or role in the pathogenesis of troponin release. The natriuretic peptides are useful prognostic markers for patients with congestive heart failure. In other patients, indefinite-duration anticoagulation should be strongly considered. The inten sity of long-term anticoagulation is controversial but will depend on the risk of both recurrent thromboembolic and bleeding events. An intravenous bolus of unfractionated hepa rin (80 U/kg) followed by 18 U/kg per hour is the standard approach to initiate anticoagulation. Overall,72 there is a trend toward reduction of mortality in favor of thrombolysis (relative risk 0. However, thrombolysis was associated with a twofold increase in the hazard of maj or hemorrhage (relative risk 1. Absolute and relative contraindications to thromb olysis are included in Tables 4 2. Catheter intervention is a promising alternative to throm bolysis or surgical embolectomy. The operation involves a median sternotomy, car diopulmonary bypass, and deep hypothermia with circulatory arrest periods. Mortality in patients with cardiogenic shock who undergo emergency surgical embolectomy approximates 30%. In the United States, a survey of 1 83 institutions found a high rate (24%) of vena caval filter insertion in patients with newly diagnosed acute deep vein thrombosis n Unfortunately, patients with filters are more than twice as likely as non-filter patients to require rehos pitalization for deep vein thrombosis owing to formation of thrombus proximal to or on the proximal tip of the filter. Occasionally, the inferior vena cava may be completely obstructed by filter thrombosis. Fracture of the filter struts with distal emboliza tion of fragments has also been reported. Temporary filters have been used in patients deemed to be at high risk for either thrombotic or bleeding events. Whenever possible, anticoagulation should be administered to prevent filter thrombosis. Jii A 20-year-old woman experienced a synco pal episode while exerting herself at work, and was trans ported to her local emergency department. At that time, she described an 1 8-month history of progressive lower extrem ity edema and dyspnea on exertion, which began shortly fol lowing surgery for repair of an ankle fracture, after which she was relatively immobile for 3 months. Initially, she ascribed the dyspnea to a combination of deconditioning and tobacco use. Twelve months later she experienced a syncopal episode while exerting herself at work, but did not seek medical at tention until 2 weeks later when she felt lightheaded and severely tachypneic. Given her severe symptoms and persistent thrombo emboli in surgically accessible locations, the patient was referred for thromboendarterectomy. Following cardiopul monary bypass and cardioplegic arrest, intimal dissection planes were created first in the right middle and lower lobe branches and multiple chronic thrombi were removed. Next, the main and left pulmonary arteries were opened and a small amount of fresh thrombus was extracted along with extensive chronic thrombi. Six weeks later she was seen in clinic and she denied dyspnea or near-syncope at any time, including during her daily exercise at the gym. Cardiac surgeons felt that she would not survive surgical embolectomy because of the prior left lung thoracoplasty. Be cause of her hemodynamic compromise, with melena on hep arin and surgical inoperability, aspiration thrombectomy was undertaken. Systemic hypotension persisted despite removal of both fresh and old clot from the pulmonary artery branches of the upper and lower right lobar arteries. The procedure was complicated by a retroperitoneal bleed, which was corrected with l2 units of packed red blood cells. She was successfully weaned from the ventilator and was transferred to a rehabilitation facility. Big endothelin- 1 and endo thelin- 1 plasma levels are correlated with the severity of primary pulmonary hypertension. Pres sure and volume loading of the right ventricle have opposite effects on left ventricular ejection fraction. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Serotonin transporter overexpression is responsible for pulmonary artery smooth mus cle hyperplasia in primary pulmonary hypertension. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Exercise-induced pulmonary hypertension associated with systemic sclerosis: four distinct enti ties. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism. Quantitative plas ma D-dimer levels among patients undergoing pulmonary an giography for suspected pulmonary embolism. N ormal 0-dimer levels in emergency department pa tients suspected of acute pulmonary embolism. The accuracy of the enzyme-linked immunosorbent assay 0-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Performance of helical comput ed tomography in unselected outpatients with suspected pulmonary and American College of Chest Physicians. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Risk stratification and outcomes in hemodynamically stable patients with acute pulmo nary embolism: a prospective, multicentre, cohort study with three months of follow-up. Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Cardiac troponin T in the severity assessment of patients with pulmonary embolism: cohort study. Incremental prognostic value of troponin I and echocardiog raphy in patients with acute pulmonary embolism. Cardiac biomarkers for risk stratifi cation of patients with acute pulmonary embolism. Low pro-brain natriuretic peptide levels predict be nign clinical outcome in acute pulmonary embolism. Comparison of con trast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Pulmonary angiography, ventila tion lung scanning, and venography for clinically suspected pulmo nary embolism with abnormal perfusion lung scan. Compression ultrasonography of the leg veins in patients with clinically suspected pulmonary embolism: is a more extensive assessment of compress ibility useful Diagnostic utility of ultrasonography of leg veins in pa tients suspected of having pulmonary embolism. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Com puted Tomography, Society for Cardiovascular Magnetic Resonance, 53. Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary em bolism. N-terminal pro brain natriuretic peptide in patients with acute pulmonary embo lism. A comparison of low molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. Enoxapa rin monotherapy without oral anticoagulation to treat acute symptomatic pulmonary embolism. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. Long-term, low intensity warfarin therapy for the prevention of recurrent venous thromboembolism. Comparison of low intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thrombo embolism. Present-day thrombolytic therapy: therapeutic agents pharmacokinetics and pharmacodynamics. Management of massive and sub massive pulmonary embolism, iliofemoral deep vein throm bosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W Heparin plus alteplase compared with heparin alone in patients with submas sive pulmonary embolism. Modern surgical treatment of massive pulmonary embolism: results in 4 7 consecutive patients after rapid diagnosis and aggressive surgical approach. A population-based study of the effectiveness of inferior vena cava filter use among pa tients with venous thrombo embolism. The role of temporary inferior vena cava filters in critically ill surgical patients. Examples include any primary insult to the myocardium: infarction, chronic volume or pressure over load, or a frank disorder of the heart muscle itself-a cardio myopathy. Cardiomyopathies are generally divided into three categories, two of which are morphologic (dilated and hyper trophic); the third one is functional (restrictive). Heart failure occurs in part owing to the adverse effects of ongoing neurohormonal activation. There is a fairly good correlation between clinical manifestations and the hemody namic profile. Patients thus evolve from being at risk for developing heart failure (stage A), to structural heart disease (stage B), to symptomatic heart fail ure (stage C), and finally to medically refractory heart failure (stage D). Cardiac catheterization is performed in patients with heart failure for several reasons: (l) to assess etiology, (2) to define both resting and exercise hemodynamic status, and (3) to evaluate therapeutic interventions. The hemodynamic profile is generally characterized in the supine state, where resting and exercise conditions can be studied (see Chapter 20), although some centers prefer measurements in the upright state, especially if exercise is being used for diagnostic or prognostic purposes. After the hemodynamic assessment has been completed, angiography should be performed to define the coronary anatomy. Clini cal criteria such as the presence or absence of angina are poor predictors of the presence or absence of clinically rele vant coronary artery disease. Noninvasive assessment of ischemic heart disease is advocated by some but can be misleading with both false positives and false negatives. The noninvasive clinical assessment may suggest a specific diagnosis such as sarcoidosis or Chagas disease, but in most instances the cause will remain undefined. Most cases of idiopathic cardiomyopathy likely represent the sequelae of prior myocarditis4 or genetic mutations. In addition to coronary angiography and biopsy, ventriculogra phy allows assessment of mitral regurgitation and dyskinesis, both of which can be targeted surgically.

The aortic obstruction was severe antibiotic to treat mrsa order ciplox amex, and the left ventricle was so decompensated that it generated a peak systolic pres sure of only 1 84 mmHg (instead of 250 to 300 mmHg virus gear generic ciplox 500mg online, as would be expected with a normal cardiac output) infection z cast buy discount ciplox 500mg line, and the mean transaortic pressure gradient was only 40 mmHg antibiotics for dogs chest infection generic ciplox 500 mg mastercard. It is no table that left ventricular dilatation is more common in men than in women with aortic stenosis antibiotics sore throat discount ciplox 500mg without prescription. The pulmonary hypertension was owing in part to the elevated left ventricular diastolic pressure (passive rise) and in part to reactive pulmonary hypertension treatment for dogs dry skin order ciplox 500mg with visa, as revealed by the finding of a pulmonary vas cular resistance of 683 dyn- second- cm-5, more than five times the normal. The pressure load on the right ventricle resulted in its decompensation, as indicated by a mild elevation of the right ventricular diastolic and right atrial pressures. Its clini cal counterparts were slight distension of the neck veins, an enlarged liver, and peripheral edema. F H, a n 8 7 -year-old man with a history of coronary artery dis ease and prior bypass surgery, was admitted to the hospital with worsening heart failure and aortic stenosis. He had un dergone coronary bypass graft surgery 6 years prior to admis sion and was not noted to have aortic stenosis at the time. Over the previous year, he had had increasingly frequent hospitalizations for congestive heart failure. His clinical pic ture was complicated by chronic obstructive pulmonary dis ease requiring home oxygen and chronic renal failure with a creatinine level that has been stable for over 6 months at 2. Echo cardiographic examination demonstrated a poor left ventricle with an estimated ej ection fraction of 35% and an estimated aortic valve area of 0. In addition to heart failure, he com plained of postprandial chest pain that responds to sublingual nitroglycerin, usually after breakfast and occurring a few times each week. He was referred for evaluation for aortic valvuloplasty owing to his high risk for reoperation in the face of multiple comorbidities. After bilateral local femoral anesthesia, a 6F sheath was placed in the right femoral artery. Iliofemoral angiography was performed on the right side, which demonstrated moderate diffuse disease in the femoral artery, but adequate for inser tion of a 1 1 F sheath for retrograde valvuloplasty. Since the femoral arterial disease precluded inser tion of a l4F arterial sheath for a larger retrograde balloon, the procedure was converted to an antegrade valvuloplasty approach. The right femoral venous access was upsized to l4F, and trans-septal puncture performed using a standard Mullins sheath and trans-septal needle. A 7F single-lumen balloon catheter was passed through the Mullins sheath into the left atrium and then into the left ventricle. The balloon catheter was then passed antegrade across the stenotic aortic valve into the arch and then into the descending aorta. The Mullins sheath was removed, and a l4F rigid dilator was passed across the atrial septum and removed. An Inoue 26-mm-diameter bal loon catheter was passed via the left atrium and positioned in the aortic valve. The balloon was inflated first to 24 mm and then to 26 mm diameter to accomplish aortic valve dilatation. The catheters were ultimately withdrawn and the femoral sheaths removed using a preplaced suture closure device. It is important to note that the peak left ventricu lar systolic pressure has declined, and the peak aortic systolic pressure has risen with the relief of aortic valve obstruction. The rise in peak aortic systolic pressure is an excellent indi cator of the hemodynamic success of balloon valvuloplasty. It is also notable that the aortic diastolic pressure has not decreased following dilatation of the valve, indicating that if aortic regurgitation has been caused, it is not hemodynami cally important. Similarly, the left ventricular end-diastolic pressure has declined from nearly 30 to 22 mmHg, indicat ing relief of obstruction with acute improvement in the filling pressures. Another approach that would also be suitable for a patient like this, with advanced age, prior sternotomy, and multiple comorbid factors causing increased surgical risk, would be percutaneous aortic valve replacement. After obtaining either antegrade or retrograde access, balloon valvuloplasty is performed to predilate the valve. Using a large-caliber sheath for delivery, the stent-mounted prosthetic (percutaneous heart valve) is crimped on a noncompliant 23- or 26-mm balloon catheter and delivered into the aortic valve. Aortography is used to document free flow into the coronary arteries, since coronary obstruction is one of the greatest risks of placing a prosthesis in the aortic annulus in this manner. Extensive experience has recently become available with this approach, and it shows excellent hemodynamic results with no residual transaortic valve pres sure gradients and valve areas typically about 1. The magnitude of regurgitation depends on the size of the regurgitant orifice, the pressure difference between the aorta and the left ventricle in diastole, and the duration of diastole. The heart may become the largest encountered in cardiac pathology-the so-called cor b ovinu m. With tim e, the fraction of end-diastolic volume ej ected per beat (ej ection fraction) diminishes, reflecting impaired myocardial function. Left ventricular workload increases pro gressively with the magnitude of regurgitation. The mitral valve may close prematurely because the regurgitating blood may raise the left ventricular diastolic pressure to exceed that in the left atrium. This reversal of pressures is associated with premature mitral valve closure, which may be seen on the echocardiogram. These tracings were recorded during cardiac catheterization of a 7 1 -year-old man who had previ ously undergone aortic valve replacement for aortic steno sis. After doing extremely well for more than 5 years, he suddenly developed marked shortness of breath and a new murmur of aortic regurgitation. As can be seen, widened pulse pressure is characteristic only of chronic aortic regurgitation, reflecting both the enormous stroke volume associated with this condition and the tachycardia commonly seen in patients with acute aortic regurgitation. This may give rise to a situa tion in which there exists a high end-diastolic pressure in the noncompliant left ventricle in the presence of little, if any, elevation of the mean pressure in the left atrium. With time and with the severity of the leak, the mean diastolic pressure of the left ventricle rises, and when this happens, left atrial and pulmonary capillary wedge pressures rise. Another hemodynamic finding in aortic regurgitation is the amplification of peak systolic pressure in peripheral arter ies (especially the femoral and popliteal) so that peak systolic femoral artery pressure may exceed central aortic pressure by 20 to 50 mmHg. This is essentially an exaggeration of a normal phenomenon (see Chapter 1 0) but emphasizes the importance of central aortic pressure measurement in aortic regurgitation. A scale of l + to 4 + may be used, with the following definitions, to aid discrimination of these four degrees of regurgitation. In l + regurgitation (mild), a small amount of contrast material enters the left ventricle in dias tole; it is essentially cleared with each beat and never fills the ventricular chamber. More contrast material enters with each diastole in 2 + (moderate) regurgitation, and faint opacifica tion of the entire chamber occurs. Part of the angiographic assessment of aortic regurgita tion involves assessment of the aortic valve leaflets (mobility, calcification, number of leaflets), the ascending aorta (extent and type of dilatation), and possible associated abnormalities. Angiography, including left ventriculography, aortography, and possibly coronary angiography (if indicated clinically). If resting hemodynamics are normal, consider stress intervention, such as dynamic exercise. Most commonly, this is caused by pulmo nary hypertension from mitral stenosis, cardiomyopathy, pri mary pulmonary hypertension, cor pulmonale, or pulmonary embolism. Organic tricuspid regurgitation implies disease of the tricuspid valve or its supporting apparatus and is seen most commonly with bacterial endocarditis, rheumatic heart dis ease, or right ventricular infarction. H emodynamic Assessment In tricuspid regurgitation, either organic or functional, the primary hemodynamic finding is a large systolic wave in the right atrial pressure tracing. Tracings of jugular venous pulsations show a, c, and v waves in the normal subj ect; in the patient with moderate tricuspid regurgitation, there is a fourth pulsation, the s wave. It is important to choose a catheter type, position, and an inj ection rate that will avoid extrasystoles because a run of ventricular tachycardia makes it impossible to evaluate the degree of tricuspid regurgitation. A scale of 1 + to 4+ is used to grade severity of tricuspid regurgitation, using criteria of definition similar to those described for mitral regurgita tion. In the most extreme cases, the right atrial and ven tricular pressure tracings are virtually superimposable, which is to be expected because the right atrium and ventricle are physiologically a common chamber in such cases. Hemodynamic distinction between organic and func tional tricuspid regurgitation is difficult. Generally, if the patient with severe tricuspid regurgitation has a right ven tricular systolic pressure of > 6 0 mmHg, the tricuspid regur gitation is functional, whereas if the right ventricular systolic pressure is 40 mmHg, there is a substantial organic compo nent. This distinction is of practical importance in terms of surgical correction, because functional tricuspid regurgita tion will improve substantially solely with correction of the right ventricular hypertension. Previously, this rare condition was seen only in patients with rheumatic heart disease and mitral stenosis. Today, however, stenosis of a prosthetic tricuspid valve (placed originally as treatment for tricuspid regurgitation) accounts for most of the cases seen in most major medical centers. Clinical diagnosis may be difficult, especially if the patient is in atrial fibrillation. Diagnosis is aided by the characteristic finding of an increased jugular venous pressure with blunting or absence of the y descent. One patient had severe stenosis of her native mitral, aortic, and tricuspid valves. This was a 4 3-year-old woman with a history of repeated bouts of rheumatic fever in child hood, whose major complaints were fatigue and "blackouts. The gradient is usually small (4 to 8 mmHg) and may be missed unless a careful assess ment is made. Tricuspid stenosis is usually of clinical and hemodynamic significance when the tricuspid valve area is < 1. Some artificial tricuspid regurgitation is seen because of the presence of the catheter across the tricuspid Angiographic Assessment the valve is usually calcified and shows decreased mobility. There may be associated right atrial dilatation and some tri cuspid regurgitation. Pul monic regurgitation is usually functional and a consequence of severe pulmonary hypertension. When the pulmonary artery pressure exceeds 1 0 0 mmHg systolic, there is usually some pulmonic regurgitation. Angiographic assessment of pulmonic regurgitation is difficult because the angiographic catheter lying across the pulmonic valve may cause artifactual regurgitation. Echocardiography is far supe rior to angiography in assessing pulmonic regurgitation. It requires knowledge of the baseline hemodynamic pro file and effective orifice area of each valve, as well as additional skills in trans-septal cardiac catheterization and, in rare cases, in the performance of direct apical puncture (see also Chapter 6). This man had mitral valve replacement with a Harken disc valve in 1 969 for rheu matic mitral regurgitation. He did well until 1 980, when he presented with left and right heart failure and was found at cardiac catheterization to have severe aortic and tricuspid regurgitation but normal function of the mitral prosthetic valve. Aortic valve replacement (Starr-Edwards prosthesis) and tricuspid valve replacement (porcine prosthesis) led to improvement, but over the following years he required large amounts of diuretic therapy to remain free of edema and pul monary congestion. Echocardiographic assessment of his prosthetic valves demonstrated apparently normal function, and left ventricular contraction was vigorous. Because of persistent left and right heart failure, cardiac catheterization was undertaken in 1 985. As can be seen, significant pressure gradients were present across tricuspid, mitral, and aortic prostheses. A surprising finding, however, was an elevated cardiac output, measured by both Fick and ther modilution methods. Using the Gorlin for mula (Chapter 1 3), the calculated aortic valve area was 1. Thyroid function tests were normal, and a search for other causes of high-output state. This patient responded nicely to thiamine supplementation, beta-block ade, and diuretic therapy with spironolactone and furose mide; evidence of high-output state receded and a vigorous diuresis ensued. Catheter Passage across Prosthetic Valves As illustrated in the case just described, it has become rou tine to cross prosthetic valves with catheters in an attempt to assess their function or the function of other valves. Based on our own experience and anecdotal experience reported to us by many others, we offer the following guidelines: First, porcine valves may be crossed retrograde or antegrade safely with a variety of catheters. For retrograde crossing of a por cine prosthetic valve in the aortic position, a pigtail cath eter is generally highly effective. Antegrade crossing of a porcine tricuspid prosthesis is accom plished easily using a balloon-flotation catheter, as described in the preceding section. The pigtail catheter also may be advanced into the left ventricle over a guidewire across a ball-valve prosthesis, but the wire should be reinserted for catheter withdrawal to avoid hooking the pigtail on the metal cage of the valve. Although some operators have crossed low-profile tilting-disc valve prostheses. Jude, Medtronic-Hall valve) retrograde without complications, instances where catheter entrapment occurred with retrograde crossing of such valves have been reported. Viking Bj ork has stated spe cifically that the Bj ork-Shiley valve must not be crossed ret rograde, based on his own vast experience. Accordingly, one should not attempt to cross a Bjork-Shiley valve or any low profile disc valve prosthesis retrograde and when a restudy is required, the trans-septal approach should be used. Patients with dual tilt disc or bileaflet mechanical valves in aortic and mitral positions present additional challenges. A 47-year-old female presented with complaints of fatigue, dyspnea, and dependent edema. At the age of 35 she had presented with severe aortic stenosis and had undergone aortic valve replacement with a St. The patient was evaluated with transthoracic and transesophageal echo cardiograms, which were suggestive of possible stenosis of the aortic valve prosthesis. There was moderate global hypokinesis with an estimated ej ection fraction of 35%. The patient was referred for evalua tion for possible re-do aortic valve replacement. Right heart catheterization and left heart catheterization through a direct apical puncture approach were then performed.

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