Future Perspectives The clinical syndrome of heart failure can be considered in terms of several different clinical model systems discount generic malegra fxt plus uk erectile dysfunction 20s, including cardiorenal trusted malegra fxt plus 160 mg goal of erectile dysfunction treatment, hemodynamic, and neurohormonal. Moreover, they do not provide an adequate scaffold for understanding newer device therapies that appear to work through neurohormonally independent mechanisms. In this regard, the emerging field of systems biology, which uses network theory to describe how the interrelationships between genes, proteins, and metabolites determine functional changes at the level of the cell, tissue, and organ, may allow investigators to accelerate the pace of novel target identification, as well as improve the likelihood of success in clinical trials. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Cardioprotective effect of apelin-13 on cardiac performance and remodeling in end-stage heart failure. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart. Phosphodiesterase 4D deficiency in the ryanodine- receptor complex promotes heart failure and arrhythmias. Pathophysiology of the cardiac late Na current and its potential as a drug target. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts: role of late sodium current and intracellular ion accumulation. Tuning the molecular giant titin through phosphorylation: role in health and disease. Prognostic value of lymphocyte G protein-coupled receptor kinase-2 protein levels in patients with heart failure. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. The relationship between myocardial extracellular matrix remodeling and ventricular function. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Targeting myocardial substrate metabolism in heart failure: potential for new therapies. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. A number of derangements in myocardial metabolism may partly explain the decrease in high-energy phosphates and phosphocreatine that have been reported in the failing heart. Although there were early reports of hepatotoxicity with this agent, hepatotoxicity occurred in patients with a genetic variant of a cytochrome P-450 enzyme (slow hydroxylation), which resulted in drug accumulation, as well as accumulation of phospholipids in the liver and nerves. The risk of toxic effects is virtually eliminated by maintaining plasma concentrations between 150 and 600 ng/mL, 3 at which levels the drug still remains effective. Importantly, maximum O uptake was increased significantly in2 both the ischemic and the nonischemic group, suggesting that the benefit of perhexiline was not entirely 4 anti-ischemic. Trimetazidine is a piperazine compound that has been widely used outside the United States as an antianginal agent. Trimetazidine has no discernible vasodilator properties at rest or during dynamic exercise and has a very favorable side effect profile. The exact mechanism of action of trimetazidine is not known, but it appears to work, at least in part, through inhibition of long-chain 3-ketoacyl coenzyme A thiolase, a crucial enzyme in the terminal steps of mitochondrial beta-oxidation. Trimetazidine has been evaluated in a number of small clinical trials in patients with 1,3 both ischemic and nonischemic cardiomyopathy. The principal mechanism of action for this drug as an antianginal remains controversial, although recent studies suggest that the antianginal effects of ranolazine may be related to decreased sodium entry into cells by inhibiting the rapid component of the + delayed rectifier K current [I ]. Although no clinical trials have yet been reported using ranolazine in patients with dilated cardiomyopathy, there are studies with ranolazine in patients with a preserved ejection fraction (see Chapter 26). Moreover, there was a small but 9 potentially concerning rise in heart rate and diastolic blood pressure in this study. Moreover, a prespecified subgroup analyses in patients with diabetes revealed no significant between-group differences. Micronutrient Supplementation The heart requires a continuous supply of energy-providing substrates and amino acids in order to maintain normal structure and function. For example, deficiencies in coenzyme Q10 (CoQ10), L-carnitine, amino acids, thiamine, and other B vitamins have been documented in the failing heart, raising the interesting possibility that micronutrient supplementation might improve the abnormal energetic milieu of the failing heart. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Cardiovascular and metabolic effects of 48-h glucagon- like peptide-1 infusion in compensated chronic patients with heart failure. Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. Although none of these is universally accepted, we use the terminology “acute heart failure” in this chapter. Although the word “acute” in the nomenclature suggests a sudden onset of symptoms, many patients may have a more subacute course, with gradual worsening of symptoms that ultimately reach a level of severity sufficient to seek unscheduled medical care. Overview of acute decompensated heart failure in Argentina: lessons learned from 5 registries during the last decade. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries: results of the sub-Saharan Africa survey of heart failure. Differences in ethnic groups have been studied most extensively in the United States and have focused primarily on differences between African American and white patients. Lower estimated mortality rates have been reported for African American than for non–African American patients, but when adjustments are made for these differences in comorbidities and age, mortality rates are similar. Although these studies can provide important insight into regional differences, they do suffer from inherent limitations and may not be truly representative of the general population because of selection bias. The growth of less selected registries in other areas of the world will provide new insights into global burden of disease. This fundamental heterogeneity complicates the attempt to create a simple and unified conceptual model. Initiating mechanisms vary according to, and interact with, the underlying substrate and may be cardiac or extracardiac.
Left ventricular aneurysms are discrete dyskinetic outpouchings of the left ventricle with preservation of the integrity of the three heart layers (endocardium malegra fxt plus 160mg free shipping gluten causes erectile dysfunction, myocardium buy cheap malegra fxt plus 160 mg on line erectile dysfunction pump, and epicardium). Spontaneous echocardiographic contrast within the aneurysms signifies local stasis of blood flow. Accuracy is undoubtedly affected by pretest probability, image quality, and the size 32 and type of thrombus (the mural type being more difficult to detect). Larger and more mobile thrombi, as well as those residing adjacent to hyperkinetic myocardial segments, are more likely to embolize. As the thrombi age, they tend to become less mobile, more compact, and echobright in appearance. C, Apical hypertrophic cardiomyopathy with midcavity systolic obliteration and an apical aneurysm. An increase in the globular shape of the heart is quantified by the sphericity index. On 2D echocardiography, this is the ratio of the long-axis dimension to the short-axis dimension. Displacement of the papillary muscle positions inferiorly and toward the apex contributes to tethering of the mitral leaflets at abnormal angles that restrict leaflet closure. A high degree of dyssynchrony, quantitated by the same 2,5,35 technique, is also a risk factor. When there is a question of whether revascularization will improve akinetic but viable areas, dobutamine or contrast-enhanced echocardiography may delineate the extent of myocardium that is 37 hibernating (hypocontractile yet viable and still perfused) (see later, Stress Echocardiography). Vasospasm, inflammation, or fibrosis secondary to myocarditis; swelling from intramural hematoma or edema; takotsubo cardiomyopathy (see Chapter 77); and any focal myocardial insult are also causes of wall motion abnormality. With persistence of the underlying condition, the left ventricle becomes less ellipsoid and more globular in shape, and the sphericity index decreases toward 1. Ischemic heart disease is often accompanied by focal wall motion abnormalities in a coronary distribution, as well as visible atherosclerotic plaque in the aortic root and other portions of the aorta. One clue to the presence of focal inflammatory processes is wall motion abnormalities that do not follow a coronary distribution and associated thickening secondary to edema. Approximately half of symptomatic patients with Chagas disease classically have an apical or inferobasal aneurysm, but more 38 advanced cases feature global hypokinesis. Takotsubo cardiomyopathy, which appears to be a stress- or neuroendocrine-mediated process, is unique in displaying a distinctive pattern of apical ballooning and 39 basal hyperkinesis in the majority (>80%) of patients (see Video 14. Although the degree of dysfunction can be impressive in stress cardiomyopathy, remarkable and complete resolution can take place within days to weeks. Rarer “reverse” or alternate patterns of stress cardiomyopathy have also been encountered, in which basal or midventricular wall motion abnormalities occur with preservation of apical function. With sustained left-sided heart failure (and thus secondary pulmonary hypertension) or systemic causes of myocardial dysfunction, the right ventricle may also become dilated and hypokinetic, and enlargement of both atria—and thus four-chamber enlargement—is also common. Historically, M-mode findings such as increased separation of the mitral E point from the interventricular septum, decreased mitral leaflet opening, and early closure of the aortic valve are known to correlate with poor cardiac output. If the patient begins to experience right-sided heart failure because of left-sided heart failure (i. Whereas chamber enlargement and systolic dysfunction are the prominent features in dilated cardiomyopathies, in hypertrophic and restrictive cardiomyopathies the ventricles are not dilated, but diastolic filling of the ventricle is impaired. Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy is a primary, genetic disease of the sarcomere in which the ventricular walls are inappropriately hypertrophied and frequently asymmetrically thickened (see Chapter 78). Such movements include the Valsalva maneuver, sudden standing, and exercise, all of which may be performed during echocardiographic evaluation of these patients. A parasternal long-axis view (left) shows markedly increased septal wall thickness and systolic anterior motion of the mitral valve (arrows), also visualized in the apical four-chamber view (right). On echocardiography this confers a “spongy” appearance to the inner layer of the myocardium, whereas the outer layer has the normal “compacted” morphology (see Fig. With noncompaction there is a spectrum of expression: the condition may affect the entire mid- and apical ventricle or merely a portion of the apicolateral wall in less affected individuals, and the severity of trabeculation may vary. Because of this variable expression and rising awareness of this entity, definitive imaging and clinical criteria continue to be refined. In general, a ratio of trabeculated/compacted layer thickness of greater than 2, as measured on 44 short-axis views at the mid- and apical levels, is considered to be consistent with noncompaction. A more specific echocardiographic criterion may be a maximal systolic compacta thickness of less than 8 mm (in the segment with the most prominent recesses), which appears to better discriminate 45 noncompaction from normal patients and those with pressure overload hypertrophy. Segmental wall motion abnormalities, including thinning and aneurysms, may be present and are caused by fibrofatty infiltration. Echocardiography alone is insufficiently sensitive or specific for the diagnosis of arrhythmogenic cardiomyopathy, and other causes of right-sided heart dilation and arrhythmia need to be excluded. Restrictive Cardiomyopathies Systemic diseases that can infiltrate the heart may lead to restrictive cardiomyopathies (see Chapter 77); the most common is amyloidosis. Advanced diastolic dysfunction is manifested both by Doppler indices and by worsening longitudinal strain measured by speckle tracking. Amyloidosis in particular has a characteristic regional pattern of severely 47 reduced longitudinal strain at the base of the left ventricle, but relatively preserved apical strain. Apart from amyloid heart disease, echocardiography is frequently used to screen for cardiac 48 involvement by other infiltrative diseases. It may reveal abnormalities ranging from dilated to restrictive phenotypes, but no specific pattern is pathognomonic of any single cause. A restrictive filling pattern may occur earlier than the manifestations of systolic heart failure. All these parameters of function have been shown to improve with iron removal therapy. Fabry disease is associated with accumulation of glycosphingolipid in the heart and a high incidence of cardiovascular signs and symptoms in addition to renal, dermatologic, and neurologic abnormalities. More than 80% of individuals with Fabry disease will display concentric hypertrophy, although concentric remodeling and asymmetric hypertrophy occur in a smaller proportion. Endomyocardial fibrosis, also termed Löffler endocarditis, is a rare restrictive cardiomyopathy frequently accompanied by peripheral eosinophilia, which may be idiopathic or associated with helminthic infection in the tropics. Eosinophilic endocarditis and infiltration of the myocardium lead to changes that can be striking on echocardiography. The ventricular cavities themselves are small with restrictive physiology because of the fibrotic process. Patients may display retracted and incompetent atrioventricular valves and marked biatrial enlargement. Because most patients are identified relatively late in the disease, the time course of development of these changes is unclear. Heart Failure Echocardiography is key in the diagnosis and management of patients with heart failure (see Chapters 25 and 26). Echocardiography can help distinguish among the different types and narrow down the potential causes of heart failure from the main categories discussed earlier.
Anal cancer can take affects approximately 2% of the population cheap malegra fxt plus express erectile dysfunction differential diagnosis, most of several forms discount malegra fxt plus 160mg overnight delivery erectile dysfunction drug warnings, such as ulcers, polyps, and verrucous whom are asymptomatic. Fetal blood remains pink; whereas maternal Intussusception blood turns yellow-brown. The Allergic Colitis child may become pale and limp, and then after the at- Allergic colitis of infancy is a diagnosis of exclusion. History may show early introduc- vention is necessary to prevent strangulation of the tion of milk or a recent episode of gastroenteritis. Laboratory studies are performed to rule out other causes such as diarrheal disease and include stool stud- Juvenile Polyps ies for leukocytes, culture, eosinophils, and complete Benign infammatory polyps of the colon are found in blood cell count. If the mother is breastfeed- experiences painless bleeding that occurs during or ing, milk and soy products are eliminated from her immediately after defecation. The anatomical location in and around the eye and the probable cause of Key Questions the disorder provide an important framework to use l Do you notice any swelling or tightness around the in assessment. The second defense mechanism is a conjunctival The orbital septum is a continuation of the periosteum immune system of lymphocytes, plasma cells, and of the bones of the orbit. Any conditions virulent organisms disrupts these normal defense occurring in these areas can cause swelling. Determining the etiology is an important and erythema under and associated with the medial step in assessing the condition. Swelling of the lids may be associated with in- fammation, local infection, or trauma. Reports of swelling, redness, and fever Key Question should alert you to these conditions. Did any liquids require immediate referral; orbital cellulitis can be splash in your eye? Chemical Injury Pain With Attempted Motion of the Eye Chemical burns of the conjunctiva and cornea represent Orbital cellulitis causes pain with movement because true ocular emergencies. Alkali burns usually result in of the collection of pus between the periosteum and the greater damage to the eye than acid burns because alkali wall of the orbit. The infammation continues to all tis- compounds penetrate ocular tissues more rapidly. Irrigate the eye with water or a saline wash for Recent Sinus Infection at least 15 minutes while obtaining a history of the Sinusitis is a predisposing condition in 86% to 98% of incident and possible chemical contact. An abrupt onset of redness typifes trauma, chemical burn, foreign body, ultraviolet exposure, or contact lens problems. Com- mon causative organisms include Staphylococcus Blunt trauma to the ocular adnexa can cause lid swell- aureus, Streptococcus pneumoniae, group A strepto- ing and/or discoloration. Rupture of the globe, frac- cocci, Haemophilus infuenzae, and Neisseria tures of the orbital bones, and internal bleeding may gonorrhoeae. Sharp trauma to the area can cause lacerations of the lid and underlying lacerations of Recurrence the globe. Internal bleeding may be subconjunctival Recurrent redness is often the result of allergic (between the conjunctiva and sclera) or intraocular conjunctivitis from a hypersensitivity reaction to (hyphema). Key Questions Unilateral redness is more likely to indicate trauma or l How long has the eye been red? Chapter 30 • Red Eye 359 A hordeolum (stye) produces redness at the base of Do I need to worry about vision changes? A chalazion is a chronic granulomatous infammation of the meibomian Key Questions gland, which is in the middle of the eyelid, often on the l Have you noticed any change in or loss of vision? Some con- l Have you had any blurred vision, double vision, ditions can present with either unilateral or bilateral halos, or foaters? Conjunctivitis often starts in one eye and then spreads to the other, sparing the limbal area of the Vision Loss eyes. Subconjunctival hemorrhage is often unilateral Distinguish vision loss from blurry vision caused but may involve both eyes. Vision is mildly out a history of signifcant trauma may indicate acute decreased in iritis but markedly decreased with acute glaucoma or keratitis with corneal ulceration. Box 30-1 lists symptom patterns of pain and vision loss (also What does the presence or absence of pain tell me? Sudden diminution in or loss of visual acuity is an Key Questions ocular emergency and may indicate corneal or uveal l Do you have pain in your eye? When Decide whether the pain is coming from the eye itself the cornea, lens, aqueous humor, or vitreous is hazy, or is referred from surrounding structures. Double Vision True double vision becomes single vision when one Severity of Pain eye is covered. Sudden onset usually indicates a Bacterial conjunctivitis causes minimal pain; most pa- tients report discomfort from the discharge and mat- ting. There may be an itching or burning pain with al- lergy, moderate pain with iritis, and severe pain with Box 30-1 Symptom Patterns of Pain and corneal abrasion or ulcer. Viral hemorrhage • Cluster • Orbital causes of conjunctivitis produce a gritty sensation in • Episcleritis headache cellulitis the eye. A scratchy sensation often accompanies condi- • Corneal • Scleritis abrasion • Corneal tions that lead to dry eye, such as Sjögren syndrome. Chronic diplopia may be Photophobia usually indicates ocular infammation or caused by muscular problems. Intraocular infammation (iritis or general- usually indicates either corneal or lens changes. This symptom Halos may be mild and often is not reported unless the patient Halos result from prismatic effects. There is signs of corneal edema caused by an abrupt rise in no photophobia with bacterial conjunctivitis. Less and young children, photophobia signals a serious con- serious causes are water drops in the cornea or lens dition, such as juvenile arthritis, intraocular tumors, (seen in corneal edema or cataract). Tears What does the presence or characteristic of the The lacrimal gland, which is situated in the upper lateral discharge tell me? Key Questions Obstruction of the passage of tears via the nasolacrimal l Do you have any discharge from your eye? Epiphora (excessive production of tears) l What are the color, consistency, and characteristics is common with viral conjunctivitis, corneal abrasions, of this discharge? Presence and Characteristics of Discharge Itching and Tearing A watery, nonpurulent or mucoid discharge usually indi- The hallmark of an allergic conjunctivitis is itching cates allergic conjunctivitis. Itching or mucopurulent may indicate bacterial conjunctivitis is intense in the spring and fall months. Viral con- Cough and Fever junctivitis discharge is watery and may affect only one Bacterial conjunctivitis is not associated with fever; eye. Corneal abrasions and ulcers also produce watery/ however otitis-conjunctivitis syndrome begins with a purulent discharge and are usually unilateral.
In femurs buy malegra fxt plus 160 mg cheap impotence age 60, a T- or Y-shaped fracture is typically seen at the distal end of the femur discount malegra fxt plus 160mg overnight delivery erectile dysfunction treatment protocol. Such fractures may occur following impaction of the end of the femur into the instrument panel in motor vehicle crashes. In angulation and compression fractures, the fracture line is curved, with an oblique component due to compression, and a transverse component due to angulation. The angulation plus rotation produces an oblique fracture, with the compression increasing the tendency toward fracture. Second, because the pelvis is a ring, disruption of any portion of it is usually associated with disruption of another portion of the ring. Complex fractures In fractures due to antero-posterior compression, there is a direct blow to either the pubic symphysis or the posterior iliac spines, or violent external rotational forces applied to the femurs. Posteriorly, there is bilateral separation of the sacroiliac joints anteriorly, with the posterior iliac ligaments generally intact. In lateral compression, the force is applied either to the iliac crest directly or to the greater trochanter by the femoral head’s being propelled into the acetabulum. However, there may be contralateral fracture of the pubic rami or, less commonly, fracture of all four pubic rami or even disruption of the pubic symphysis. Posteriorly, there is ipsilateral impaction of the sacroiliac joints with the posterior ligaments generally intact. If the femoral head produces lateral compression by being propelled into the acetabulum, there are usually ipsilateral fractures of the pelvic rami, disruption of the sacroiliac joints with impaction, and fractures of the acetabulum. The force is perpendicular to the trabecular pattern of the posterior pelvic com- plex, which results in disruption of both the anterior and superior sacroiliac ligaments with gross disruption of the joints. Anteriorly, there may be disruption of the pubic symphysis, two pubic rami, or all four pubic rami. In complex fractures, multiple forces from different angles have been exerted at the pelvis and one cannot simply classify the injuries as being due to the three aforementioned modes. Healing of Fractures Healing of fractures depends on the ages of individuals and their nutritional status. Fractures of Blunt Trauma Wounds 115 cancellous bone unite faster than those of cortical bone. The bone is consoli- dated in 4–6 weeks, though it usually takes 2–3 months to heal solidly. In adults, consolidation takes approximately 3 months, though in the case of the femur, it could take 4–5 months. In healing, fractures of the bone undergo a number of stages that end in repair of the bone. Initially, there is hemorrhage at the point of fracture secondary to rupture of vessels, with production of a fusiform hematoma surrounding and joining the ends of the bone. The periosteum is torn from the outer surface of the bone; the endosteum from the marrow. This is followed in 24 to 48 hours by an inﬂam- matory response with edema, continuing deposit of ﬁbrin and the accumu- lation of large numbers of polymorphonuclear cells. The next stage begins 48 hours after injury and is characterized by the appearance of ﬁbroblast and mesenchymal cells with gradual development of granulation tissue. Necrosis of the bone adjacent to the fracture becomes evident, with empty lacunar spaces due to death of osteocytes. The line of demarcation between dead bone, with its empty lacunae, and live bone is evident. There is marked proliferation of the cells of the deep layer of the periosteum and, to a lesser degree, of the cells of the endosteum. As the days pass, the periostial proliferation results in formation of a collar around what is becoming the callus. At the same time the periosteal cells are proliferating, capillaries begin to grow out into the hematoma. Approximately a week after injury, granulation tissue, ﬁbroblasts, osteoblasts, chondroblasts and small islets of cartilage in the ﬁbrous stroma appear. Osteoblasts produce a matrix of collagen and polysaccharide, which becomes impregnated with calcium to produce immature “woven” bone. The next stage appears in 3–4 weeks and is marked by a hard bony callus, with the bone forming from periostial and endochondrial ossiﬁcation. In the last stage, there is remodeling of the new bone from a woven appearance to mature bone. Robertson I, Antemortem and postmortem bruises of the skin: Their differ- entiation. Presented at the Annual Meeting of the American Academy of Forensic Science, Nashville, February 19-24, 1996. Blunt Trauma Injuries of the Trunk 5 and Extremities Blunt Force Injuries of the Chest The thorax, or chest, is a bony-cartilaginous cage containing and protecting the heart, the lungs, and their major blood vessels. The posterior surface (the back) is formed by the 12 thoracic vertebrae and posterior aspect of the ribs. The sides are formed by the ribs, separated from each other by the intercostal spaces, 11 in number, which are occupied by the intercostal muscles. The diaphragm forms the ﬂoor of the chest cavities and separates the thoracic from the abdominal cavities. The heart lies between the two lungs in the middle of the chest, enclosed within a sac, the pericardium; each lung is enclosed by a serous membrane, the pleura. The heart is placed obliquely in the chest behind the body of the sternum and adjoining parts of the ribs. It projects farther into the left chest cavity than the right, such that about one third of it is situated to the right and two thirds to the left of the midline. Nonpenetrating blunt force injuries of the chest organs can occur with or without external evidence of injury to the chest wall. In some cases, the absence of external injury is attributed to the clothing worn by the victims. Children and young adults, whose chests are pliable and elastic, may sustain severe injuries to the intrathoracic viscera without fractures of the sternum and ribs, whereas in older people, fractures of the ribs and sternum are frequent. In the elderly, and in chronically debilitated or malnourished individuals, the ribs are fragile and easily broken when minimal pressure or violence is applied to the chest. These fractures usually involve the ﬁrst six ribs, tend to be more left sided than right, and are either anterolateral or anterior. Depending on where the force is applied, one or more of the underlying ribs might be frac- tured. If severe localized direct force is applied to the chest, the fractured ribs can contuse the underlying lung parenchyma or the sharp, pointed fragments of rib can be driven into the pleural cavity, lacerating the pleura, lung, or heart, resulting in pneumothorax or hemopneumotho- rax.