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Light touch includes three other phenomena: The general senses include light touch or tactile two-point sense buy cytotec us medications pain pills, stereognosis purchase on line cytotec medications with weight loss side effect, and graphes- discrimination and sensations of pressure or deep thesia purchase cytotec toronto medications nursing. Two-point sense is the ability to distin- touch, vibration, proprioception, pain, and tem- guish stimulation by one or two points applied perature. The minimal distance between three neurons: number 1 in the sensory ganglia, the two points that can be felt separately var- number 2 in the spinal cord or brainstem or both, ies considerably on different parts of the body. Two points can be distinguished as close as 1 mm 132 Chapter 11 The Somatosensory System: Anesthesia and Analgesia 133 on the tip of the tongue and 2 to 4 mm on the movement. Position sense can be tested by pas- fngertips, whereas on the dorsum of the hand sively moving a limb or one of its parts to a cer- two points closer than 20 to 30 mm cannot be tain position and having the subject move the distinguished from one another. A patient the ability to recognize objects by touch alone, who can stand with the feet together and the eyes using the object’s size, shape, texture, weight, open, but who sways and falls when the eyes are etc. Graphesthesia is the ability to recognize closed, has the Romberg sign, which indicates an numbers or letters drawn on the skin. Both ste- absence of position sense in the lower limbs (see reognosis and graphesthesia require intact light Chapter 13). Pain There are two types of pain or nociceptive (noci means noxious) sensations: fast and slow. Fast Pressure pain is of the sharp, pricking type and is well The perception of pressure involves stimuli localized. Pressure by alternately touching the tip and head of a sense is tested by frmly pressing on the skin with safety pin to the surface of the skin. The patient a blunt object and by squeezing the subcutaneous should be able to readily distinguish the sharp- structures and muscles. Pressure sensations are ness of the tip of the pin from the dullness of the often referred to as deep touch. Vibration Sense Itch was formerly associated with pain- When the shaft of an oscillating high-frequency conducting nerve fbers, but is now thought (256 vibrations per second) tuning fork is gently to occur via a separate group of very slow con- applied to the skin overlying the bony promi- ducting nonmyelinated fbers with histamine nences, vibrations in the subcutaneous tissues are receptors. Vibration sense, therefore, requires intact pathways from deep structures such as Temperature subcutaneous connective tissue, periosteum, and muscle. Temperature sensations range from cold to cool When an oscillating low-frequency (128 vibra- to warm to hot and are tested by touching the tions per second) tuning fork is used, the sensa- skin with test tubes flled with either cold or tion is described as “futter” or fne vibrations in warm water. With axon, which bifurcates into a peripheral branch eyes closed, the subject should be able to rec- and a central branch. Rapidly adapting mech- peripheral branch enters the spinal or cranial anoreceptors signal the onset and cessation of a nerve and eventually terminates as an ending stimulus and are important for sensing movement that responds to a specifc type of stimulus. Discrete tactile stimula- encapsulated sensory nerve endings transduce tion is detected by Merkel discs and Meissner the physical stimulus into electrical receptor corpuscles located in superfcial layers predomi- potentials that encode stimulus strength and nately in glabrous skin. The corpuscles are encapsulated by many fattened cutaneous area over which a receptor is acti- epithelial cells. The size of est receptive felds and most importantly signal receptive felds for the same receptor types var- discrete indentations of the skin. Merkel discs ies in different parts of the body, generally being also provide information about the curvature smallest at the tips of the fngers and perioral of objects. The principal to abrupt changes in the shape of the edges of somatosensory receptors and their functions are objects or irregularities on the surface of objects. Displacements of adjacent hairs activate different hair follicle receptors provid- Tactile Receptors ing additional information to the brain about dis- Tactile stimulation activates encapsulated mech- crete tactile stimulation. Pacinian generation of action potentials in the primary corpuscles have relatively large receptive felds afferent axons. Ruffni endings sense stretching rate increases proportionally to the intensity of the skin and provide information about the of the potentially destructive stimulus and shapes of objects. Thermal nocicep- tors signal noxious heat (above 45°C) or cold Temperature Receptors (below 5°C) temperatures. Polymodal nocicep- Cold, cool, warm, and hot sensations below tors respond to any destructive mechanical, and above normal skin temperature (34°C) thermal, or chemical stimuli resulting from are sensed by thermoreceptors. Cold receptors tissue damage and are the underlying basis for fre most vigorously about 10°C below normal the sensation of slow, burning type of pain. The nerve fbers conducting general sensations vary in their sizes or diameters and in their con- Pain Receptors duction velocities. The nerve fbers The area of skin supplied by the somatosen- conducting tactile, pressure, vibration, and pro- sory fbers from a single spinal nerve is called a prioception sensations are larger and faster con- dermatome (Fig. Although there is overlap ducting than are those nerve fbers conducting between the dermatomes, they are very useful in pain and temperature impulses. The dermatomes Nerve fbers are classifed in two ways, by con- essential to know for neuroanatomy problem duction velocity and by diameter. Nerve fbers are solving are C2, back of the head; C5, tip of the classifed according to conduction velocity as type shoulder; C6, thumb; C7, middle fnger; C8, A, B, or C, with A indicating the fastest conduc- small fnger; T4 or T5, nipple; T10, umbilicus; tion velocity and C the slowest. Strong A series of three neurons transmits the touch stimuli generate larger receptor potentials, system impulses from the mechanoreceptors in which are coded as a greater number and higher the periphery to the cerebral cortex, where these frequency of action potentials. Even then First-Order Neurons adaptation occurs with a constant stimulus of relatively long duration. The larger, fast-conducting unipolar neurons in the dorsal root or spinal ganglia are the pri- mary touch, vibration, and proprioception neu- rons. The central branches enter the spinal cord Clinical through the more medial parts of the dorsal roots Connection (Fig. As the entering touch duction velocity of the larger touch and proprioception fbers turn to ascend, they fbers and smaller pain fbers in peripheral nerves give branches that enter the spinal gray matter allow the selective electrical stimulation of one for refex and pain modulation purposes. In the cervical Clinical segments of the spinal cord, the two tracts are Connection partially separated by the posterior intermediate Because the gracile and cuneate septum. Some shift- ing occurs in the rostral half of the spinal cord Second-Order Neurons because the sacral fbers here occupy most of the dorsal part of the dorsal column and hence tend The axons of the gracile and cuneate tracts to be spared when the central part of the spinal terminate at the secondary somatosensory neu- cord is damaged. The axons from the dorsal column limb is represented laterally and the contralateral nuclei cross the midline as the “sensory decussa- upper limb medially. The proprioceptive fbers are more ventral contralateral upper limb is represented approxi- in the dorsal columns and synapse more rostrally mately in the dorsal half of the postcentral gyrus, in the nuclei. At this point, the lower Anatomical and clinical evidence indicates that limb is represented laterally and the upper limb the fast and slow pain paths are dissimilar. Slow pain, how- ever, is transmitted by phylogenetically older neurons that form the paleospinothalamic and Clinical spinoreticulothalamic systems. The level of the dorsal column A series of three neurons transmits fast pain nuclei and sensory decussation and temperature impulses from the receptors in is of medical signifcance because a unilateral the periphery to the cerebral cortex where these lesion that interrupts the impulses before they sensations are perceived (Figs. However, a unilateral lesion beyond the sensory decussation, that is, a lesion in the The smaller, slower conducting unipolar neu- medial lemniscus or subsequent structures in rons in the dorsal root or spinal ganglia are the the path, results in the loss of these sensations primary neurons for the pain and temperature contralaterally. The cen- tral branches of their axons enter the spinal Chapter 11 The Somatosensory System: Anesthesia and Analgesia 139 To primary sensory cortex Lower Upper limb limb fibers fibers Posterior limb Ventral internal posterolateral capsule nucleus (3° neurons) Thalamus Midbrain Upper limb: medial Lower limb: lateral Pons Medial lemniscus Upper limb: posterior Medulla Lower limb: anterior Level of sensory decussation Cuneate nucleus Dorsal 2° column neurons Gracile nucleus nuclei Internal arcuate fibers Cuneate tract (upper limb) Gracile tract (lower limb) Spinal ganglion 1° neuron Figure 11-3 Three-dimensional drawing of dorsal view of dorsal column-medial lemniscus system (1°, primary or frst order; 2°, secondary or second order; 3°, tertiary or third order). Left hemisphere Paracentral lobule Internal capsule (posterior limb) Lower limb region Ventral posterolateral thalamic nucleus Upper limb region (3° neurons) Superior Postcentral gyrus colliculus Rostral midbrain Medial lemniscus Medial lemniscus Trigeminal nerve Midpons Medial lemniscus Rostral medulla Dorsal Gracile nucleus 2° neuron in dorsal column nuclei column nuclei Cuneate nucleus Internal arcuate fibers Level of sensory Caudal medulla decussation Cuneate tract 1° neuron in cervical spinal ganglion Gracile tract Cervical cord 1° unipolar ganglion cells Lumbar cord Figure 11-4 Schematic diagram showing the touch system pathway from spinal nerves.

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In addition generic 200 mcg cytotec otc treatment shingles, you should contact the local media to advise citizens to take precautionary measures against inclement buy cytotec mastercard medicine 4839, cold weather buy cytotec in united states online symptoms checker, such as wrapping water pipes, ensuring that resources are at hand to properly keep their house heated, and having plenty of provisions for food and water. Since the bad weather can paralyze communications and transportation, you need to be sure to have the proper resources on hand to clear the roads as well as repair any telecommu- nication lines. Additionally, shelters should be made ready to receive homeless persons that will need a place to stay during the cold snap. Medical facilities and personnel should be placed on full alert for potential patients. Stage 2 of the Disaster You are receiving reports that ships in the channel are sinking, and you now have a food shortage, since all the dairy and food supplies are stuck on railroad cars that are inaccessible (Ohio Historical Society, 2006). The city manager should direct any maritime rescue units to perform search and rescue operations for ships that are sinking in the channel. A high priority should be given to both getting the communi- cation lines repaired and clearing the roads so that food and water shipments can be made to people that are unable to get supplies. Consider using any type of transportation that does not need roads to make food and water deliv- eries to residents. The city manager should send out communication to all ships that are in the channel to dock until the storm has passed. In addition, the city manager should attempt to communicate with surrounding areas to see what resources are available to help with infra- structure repair as well as attempt to gain more resources from other local municipalities and state and federal entities. The city manager should begin to recruit any engineers or salvage experts that can be found to assist with repairing ships that are currently sinking. In addition, if harbor tugboats are available, those ships can be used to tow any distressed vessel to port until repairs can be made. Stage 3 of the Disaster The winds have now picked up and are gusting to over 74 miles per hour (Dallaire, 2004). You have learned that 235 sailors have now died and 12 ships have sunk (Ohio Historical Society, 2006). The good news is that farmers are delivering dairy and food supplies with sleds drawn by horses (Ohio Historical Society, 2006). You have asked the Boy Scouts to clear fre hydrants of snow in case fres break out. Fire is a concern because several buildings have collapsed and the roads are impassable (Ohio Historical Society, 2006). The city manager should seek out medical supplies and medical personnel as well as morticians to contend with the rising death toll. Clearing the roads is becoming very critical, not only for food and water deliveries, but also to allow frst responders to respond to fres that could break out and allow passage for ambulances that need to get to patients. You will need to redouble your eforts on getting assistance to the harbors for the ships that are in danger of sinking and evacuating crews that are freezing and starving to death. Tere may need to be temporary shelters constructed as well as more provisions being trans- ported into your city. To do this, the city manager should reach out to organi- zations such as the American Red Cross, as well as federal and state agencies that can assist the community in times of need. What areas should you focus on for assistance to the citizens and ships after the storm has occurred? The city manager will need to focus on water, food, medical, and housing needs for the citizens. For the sailors, the city manager will need to provide assistance getting those individuals food and water as well as assistance in getting their ships repaired or salvaged in order to clear the harbor. Key Issues Raised from the Case Study The Great Lakes storm was one of the largest storms to ever hit the Great Lakes. With hurricane-force winds, it caused 250 fatalities and $5 million in damage (McLeod, 2011). The case study illustrates the need to prepare for isolation in the event of a major winter storm. Stockpiles of food, medical supplies, and fuel Case Studies: Disasters from Natural Forces—Floods ◾ 65 should be kept on hand in case transportation links are cut for any length of time. Additionally, it is important to establish an efective communication link with all entities in and around the area so that preventative measures can efectively be taken. The single biggest failure in this case study was not maintaining a stockpile of supplies for such an event. The second biggest failure was not ordering the ships out of the area before the full force of the storm was felt, nor evacuating the sailors from the damaged ships. However, the modes of communication available in 1913 may have prevented efective notifcation to the ships that were out of port. Items of Note Twelve ships were lost and fve remain unaccounted for to this day (Dallaire, 2004). Banqiao Dam Flood, China, 1975 Stage 1 of the Disaster You are an emergency management coordinator in charge of safety and disaster management for the Henan Province in China. The Banqiao Dam and many other dams were constructed beginning in the 1950s under a government program (Watkins, 2012). In your province, the area is considered rural, with many small towns that are densely populated compared to cities in Europe or the United States (Zhao, 2012). In many towns along the river system, telephones are the excep- tion to the rule, with most towns having no modern means of communication (Zhao, 2012). On the Banqiao Dam in particular, your government has received assistance from the Soviet Union to help reinforce and modify the dam to make it stronger than what was originally designed (Watkins, 2012). You are confdent that the dam is sufcient since the modifcations have taken place and the dam has been developed for a 1,000-year food (Watkins, 2012). It is now August and you have just seen the forecast, which is projecting a typhoon that is coming toward Henan Province. The emergency management coordinator should begin to get estimates on how much water the storm could potentially pro- duce to see if the dams could contain that much water. Additionally, since you do not have a reliable or a limited modern communication system, you will need to establish some type of reliable and fast communication system. With the possibility of a typhoon com- ing toward your province, you should communicate with the towns along the river that there is a storm coming and that each town should have an evacuation plan available and publicly posted so the community will know what to do if evacuation is necessary. In addition, you should have a system 66 ◾ Case Studies in Disaster Response and Emergency Management of runners or couriers on standby in case there are problems with the dam’s capacity, which would allow water to overfow or ultimately break the dam. Having time to evacuate is critical for a town’s survival if something does go wrong with the dam. Furthermore, you need to establish close contact with personnel at the dam, local and central government fgures, and personnel that monitor weather conditions. With only a limited modern tele- communication system available, you will need to recruit and train couriers who can deliver notices to evacuate to the towns and villages that will be impacted if a food does occur. You will also need to assist towns with evacu- ation plans for their communities, which can increase the survival rate of their citizens. Stage 2 of the Disaster The rain is falling more than was originally forecasted, and instead of a 1,000-year food, which the dam was designed to contain, the rainfall is for a 2,000-year food, which is far above what the dam was constructed to withhold (Watkins, 2012).

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The patch patch and augmentation of the inferior end of the ventricu- should be suffciently wide that the main pulmonary artery lotomy with the heel of the patch discount cytotec 100 mcg amex medicine to stop vomiting. The placement of sutures has a normal appearance when subsequently distended with is begun at the toe of the patch using continuous 6/0 or 5/0 blood purchase 100 mcg cytotec amex medications you can take while breastfeeding. There may be a fbrous rim in this area which may represent a remnant of the membranous septum order cytotec 200 mcg with amex treatment concussion. This is particularly critical at Avoidance of Coronary Injury by Sutures the level of the annulus. The patch should widen somewhat as In the neonate and small infant, it is usually preferable to it extends on to the ventricle, so that it is pear shaped. At the leave the aortic cross-clamp in place until the patch suture apex of the ventriculotomy particularly wide bites should be line is well beyond coronary arteries because they are at risk taken on the patch, while bites should be very closely spaced of being caught up in the suture line. In the older patient, for ventricular branch extending from the right coronary to the example a teenager or young adult, cyanosis may be less well apex of the heart. Placing the suture line very close (1–2 mm) tolerated than by the infant so care must be exercised to avoid to a coronary artery risks causing coronary ischemia through leaving an excessively large atrial communication. An alternative is to place sutures inside out from the endocardium with small pledgets lying Weaning from Bypass within the right ventricle if necessary. A low dose mattressed safely under a coronary artery if the ventricu- dopamine infusion at 5 μg/kg/min is often useful. Leaving a small portion of the suture line open at the time the aortic Residual Right Ventricular Outfow Tract Obstruction cross-clamp is removed will allow decompression of both the Residual right ventricular outfow tract obstruction is eas- right and left heart until ejection commences. When the heart ily detected with simultaneous monitoring of a pulmonary is beating effectively, the suture line can be tied. Right ventricular Monitoring Lines and Pacing Wires outfow tract obstruction severe enough to produce supra- Following de-airing of the heart and release of the cross- systemic right ventricular pressure is the most likely reason clamp, a left atrial line is inserted through a mattress suture for failure to wean from bypass. A right ventricular pressure in the right superior pulmonary vein, as described previously. In addition, pullback of the use of both two-dimensional imaging and Doppler analysis. However, today, a pulmonary artery line is reserved for can be used to quantitate the pressure gradient. In the early postoperative period, the right gradient will occur if the Doppler beam cannot be aligned ventricle is likely to be the limiting factor for total cardiac parallel to the area of peak velocity within the outfow tract. There has also been considerable retraction of tion for a return on bypass to extend the outfow patch across the right ventricle during the period of myocardial ischemia, the annulus. A high will be characterized by an elevated left atrial pressure and right atrial pressure, for example, more than 10–12 mm, is systemic hypotension. Normally, right atrial pressure would poorly tolerated by the neonate and young infant and will be expected to be higher than left atrial pressure in the imme- result in a “leaky capillary syndrome. The diagnosis can be confrmed who is adapted to the low oxygen environment of the prena- by demonstrating a marked step up in the oxygen saturation tal circulation. Cardiac output is maintained, urine output is of blood taken from the right atrium (e. In the child between about 4 and were undetected may become detectable once the repair 10 kg, the annular diameter in millimeters needs to be at is completed and right ventricular pressure is subsystemic. The peripheral pulmonary arteries are thin walled and distensible and pulmonary vascular resistance is gener- early mortality ally not elevated. An acute volume load is particularly poorly All patients were less than 90 days of age, with a median tolerated in the setting of diastolic dysfunction. Of the 99 patients, 59 were prostaglandin Restrictive right ventricular diastolic physiology may dependent. Overall 91% of patients were considered symp- occur in older patients as the result of the concentric hyper- tomatic because of cyanosis with or without cyanotic spells. The results from Children’s Hospital Boston are simi- lar to those from several other groups. There were Coronary Obstruction and Rare Coronary Anomalies If two hospital deaths for a hospital mortality of 0. In an the outfow tract patch suture line has passed extremely close important study described by Kirklin et al. The authors concluded malities (hypokinesis, akinesis) will further confrm this sus- that there was a possible disadvantage for the two-stage picion. It may become necessary to return on bypass, take approach employing preliminary shunting and later repair. When this is lonG-term results after early primary repair undertaken, it is useful to use interrupted pledgetted sutures with the pledgets lying on the endocardial surface of the free In 2001, Bacha et al. Retraction of the main pulmonary artery to view the up was obtained for 45 of the 49 long-term survivors. Although there were eight early Retrograde fow in the left main, as well as evidence of papil- deaths in this early timeframe, there was only one late death lary muscle fbrosis, may alert the echocardiographer to the 24 years after the initial repair. There was no infuence of a transannular patch on Transatrial Approach to Repair of late survival (Fig. The majority of reintervention procedures which obstruction is secondary to moderately hypertrophied muscle 10 patients underwent were for recurrent right ventricular out- bundles rather than generalized hypoplasia of the infundibu- fow tract obstruction which was necessary in eight patients. There is a trend toward a higher rate of reintervention for patients who did not have transannular patch. Other reinterventions included one patient who had a homo- graft pulmonary valve replacement 20 years postoperatively primary versus two-staGe repair performed at another institution and one patient who required a defbrillator for inducible ventricular tachycardia. A small number of centers continue to support an approach Long-term follow-up studies from other centers have of initial palliation with a modifed Blalock shunt in the suggested that residual or recurrent right ventricular out- frst 6–12 months of life followed by subsequent repair3,4 fow tract obstruction is a more serious late problem and a and have been able to achieve excellent early results with more common cause of need for reoperation than pulmonary this strategy. Chen and Moller67 followed 144 patients for 10 underwent a right ventricular infundibular sparing strat- years. They found that patients with right ventricular outfow egy between 1995 and 2008 at Texas Children’s Hospital. Postoperative morbidity reviewed 106 patients who underwent repair of tetralogy at included arrhythmias (3% [10]), postoperative bleeding the University of Minnesota between 1954 and 1960. Similar (2% [7]), temporary renal failure (1% [3]), and neurologic to the experience from Boston, the commonest cause for reop- injury (<1% [2]). Overall eration was recurrent right ventricular outfow tract obstruc- 1- and 7-year Kaplan–Meier survivals were 97 and 96%. For with the mandatory reintervention required with a two- example, this was true in the two institutional study reported stage approach. For exam- of Alabama with an approach of early primary repair as prac- ple, in a 1997 report by Gladman et al. In fact, a high postrepair patients who had a two-stage approach at the Hospital for Tetralogy of Fallot with Pulmonary Stenosis 363 Sick Children in Toronto was 90%, while in patients who had replacement. The latter when indexed to body surface area is currently con- sidered the best measure for proceeding with valve replace- transatrial versus transventricular repair 2 ment. Currently, an indexed volume of 150–165 mL/m or A number of studies have presented excellent results using a greater is considered an indication to operate. Reoperation for right ventricular outfow obstruction was more common in the latter phase of the study, presumably Although some centers have expressed enthusiasm for place- as the strategy of infundibular sparing was more aggres- ment of a monocusp valve at the time of initial tetralogy sively applied.

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A bicuspid aortic valve is present in 30% of patients with Turner syndrome order cytotec no prescription symptoms zinc overdose, and clinically significant aortic disease (coarctation cytotec 100 mcg sale symptoms vertigo, aortic stenosis) is found in approximately 10% of affected newborns (102) buy discount cytotec on line treatment definition. Another chromosomal disorder linked to aortic valve disease is 11q terminal deletion disorder, also known as Jacobsen syndrome. More than half of patients with Jacobsen syndrome have congenital heart disease, with approximately 18% of patients having left-sided obstructive lesions (103). The critical region on 11q for left ventricular outflow tract development has not yet been identified, and the gene deletion(s) responsible for left heart obstruction in this setting are not yet known. Each of these genes is related to a syndrome known to include bicuspid aortic valve as part of its phenotype (Table 44. Supplementation with nitric oxide has been shown to prevent calcification of aortic valve interstitial cells in vitro (109), while nitric oxide deficiency is associated with bicuspid valve formation in mice (109). This suggests interaction between the two pathways in aortic valve morphogenesis (110). One intriguing potential connection between nitric oxide and aortic valve development involves the observation that mechanical factors, such as decreased flow in developing hearts, can contribute to abnormalities of the aortic valve and left ventricular outflow tract. Similarly, the unique geometry of a bicuspid aortic valve has also been shown to result in alterations in shear stress compared to a tricuspid aortic valve (115), and this is thought to contribute to the early development of calcific aortic stenosis in bicuspid valves. Subvalvar Stenosis Though often considered an acquired condition, several familial clusters of discrete subvalvar aortic stenosis have been reported, suggesting a genetic basis of disease in at least some cases. While no causative genes have been identified, inheritance patterns suggest autosomal recessive transmission may be involved in some instances. Of the ten families with inherited discrete subvalvar stenosis reported in the literature, four consisted of unaffected consanguineous parents with multiple affected children, consistent with autosomal recessive inheritance (116,117,118). The remainder of the reported pedigrees were suggestive of autosomal dominant inheritance, but limited numbers of affected individuals within the pedigrees make interpretation difficult (118). While the existence of these family clusters indicates that genetic factors play a role in the development of subvalvar stenosis in some instances, the rarity of these familial cases suggests that the heritability of subvalvar stenosis is in general far less than either valvar or supravalvar aortic disease. One additional piece of evidence suggesting some genetic influence in the development of subvalvar stenosis is the overrepresentation of bicuspid aortic valve (up to 25%) among patients with subvalvar obstruction (37). As discussed previously, bicuspid aortic valve is a highly heritable condition, with an overall prevalence of approximately 1% in the general population. The relatively high prevalence of bicuspid aortic valve among patients with subvalvar stenosis strongly suggests a genetic component in susceptibility to the disease. Given the hypothesized role for abnormal flow and shear stress in the formation of subvalvar membranes, however, it may simply be that any abnormality of the left ventricular outflow tract that provides a substrate for nonlaminar flow may result in membrane formation. Supravalvar Stenosis The molecular genetics of supravalvar aortic stenosis have been fairly well described. As discussed above, aortic disease is the most prominent manifestation of a systemic arteriopathy. Supravalvar aortic stenosis has been traditionally associated with Williams–Beuren syndrome (61,74,119), a syndrome in which the arteriopathy is accompanied by cognitive disability, distinctive “elfin facies,” hypocalcemia, small stature, and an ebullient personality (69). Identical vascular pathology is also seen in the absence of the other findings of Williams– Beuren syndrome, however, both in inherited and sporadic forms (120,121). Familial supravalvar aortic stenosis is generally inherited as an autosomal dominant trait. Williams–Beuren syndrome is now known to be caused by a microdeletion of approximately 1. Physiology The primary physiologic derangement in aortic stenosis and its subtypes is left ventricular outflow tract obstruction. While the location and mechanism of obstruction may affect disease course and treatment options, the essential pathophysiology is the same whether the stenosis is above, below, or at the level of the aortic valve. In all cases, obstruction to flow creates increased afterload for the left ventricle with a variety of downstream consequences. Assuming preserved left ventricular systolic function and cardiac output, left ventricular outflow tract obstruction results in increased left ventricular systolic pressure and wall stress. Ventricular wall stress is directly proportional to ventricular pressure, and inversely proportional to ventricular wall thickness. Myocardial hypertrophy is, therefore, initially a compensatory response, causing increased wall thickness that at least temporarily maintains constant wall stress in the face of increasing ventricular pressure. Careful hemodynamic studies have demonstrated that concentric ventricular hypertrophy in response to aortic stenosis successfully maintains wall stress within normal limits throughout the cardiac cycle despite significantly elevated ventricular systolic pressure (128), and may actually lead to decreased wall stress at rest compared to healthy controls (129). Over time, however, a persistent pressure load on the left ventricle results in pathologic ventricular remodeling with the eventual development of clinical heart failure. The mechanism by which compensatory hypertrophy progresses to heart failure is not entirely understood, but it is clear that there are gradual changes in the myocardium at the cellular level that lead to a typical sequence of hemodynamic consequences (130). As changes on the cellular level progress from myocyte hypertrophy to fibrosis and cell death, there is a progression of hemodynamic sequelae from initial mild abnormalities of diastolic function to eventual severe combined systolic and diastolic dysfunction (131,132). The first negative physiologic effect of ventricular hypertrophy is impaired ventricular relaxation (131,133), with decreased ventricular filling in early diastole. Impaired relaxation occurs independently of systolic dysfunction, and is correlated with the degree of ventricular hypertrophy (133,134,135). While significant fibrosis can be identified in patients with preserved systolic function (136), progressive fibrosis is associated with increased ventricular stiffness as well as eventual systolic dysfunction (130,137). In addition to the effects of fibrosis, myocyte death also begins to occur, likely largely through nonapoptotic cell death pathways (130). Over time, progressive cardiomyocyte loss and degradation with increased collagen replacement of myocytes results in continued deterioration of systolic and diastolic function and the eventual development of clinical heart failure. Another contributor to myocardial dysfunction in left ventricular outflow tract obstruction is the development of subendocardial ischemia. Because high intracardiac compressive forces in the subendocardium limit systolic coronary artery flow, the majority of oxygen delivery to the subendocardial myocardium occurs during diastole, when the gradient between the aortic and left ventricular diastolic pressures creates a driving force for coronary artery perfusion (138,139). In the normal heart, increased myocardial oxygen demand can be met by increased coronary blood flow and oxygen delivery via coronary vasodilation. The capacity for increasing coronary blood flow in response to increased demand is referred to as the coronary flow reserve. In patients with severe aortic stenosis, the coronary arteries are almost maximally dilated at baseline with little ability for additional vasodilation, which translates to minimal coronary flow reserve (140). Subendocardial oxygen delivery in patients with significant aortic stenosis is therefore largely determined by the duration of diastole as well as the driving pressure for diastolic coronary artery blood flow, represented graphically by the area between the aortic and left ventricular pressure tracings during diastole (Fig. Hemodynamic data from a cohort of 80 pediatric patients with aortic stenosis demonstrated that the myocardial supply to demand ratio is affected by three primary factors: aortic valve area, diastolic function, and heart rate (139). Left ventricular end-diastolic pressure and heart rate were both significantly correlated with the adequacy of subendocardial oxygen delivery. Heart rate, and more specifically the duration of diastole, appeared particularly important; all patients with severe aortic stenosis and a heart rate of <100 demonstrated adequate oxygen delivery, while only one patient with severe stenosis and a heart rate of >100 had a supply to demand ratio of >10. These data suggest why tachycardia may be poorly tolerated in patients with severe aortic stenosis.