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Beta Blockers 31 Beta blockers have largely fallen out of favor for routine use as antihypertensive therapies and in patients with diabetes purchase ondansetron in united states online treatment models. For patients with aspirin indication but with aspirin allergy or intolerance cheap ondansetron master card medications requiring prior authorization, P2Y12 receptor antagonists may be considered cheap ondansetron 4 mg online medicine dispenser, such as clopidogrel, prasugrel, or 13,15 ticagrelor. These agents are often used in combination, typically two or three drugs, to reduce hyperglycemia. Pancreatitis Alogliptin concentrations (glucose-dependent) Possible ↑ heart failure Linagliptin (saxagliptin; alogliptin) Bile acid Colesevelam Binds bile acids in intestinal Unknown No hypoglycemia Generally modest HbA1c efficacy High sequestrants‡ tract, increasing hepatic bile? Mitogenicity/cancer risk Aspart Injectable Glulisine Training requirements Glargine “Stigma” (for patients) Detemir Degludec Premixed (several types) * Not licensed in the United States. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach—update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Cardiovascular Effects of Selected Medications for Diabetes Until 2008, the approval of drugs for diabetes depended almost exclusively on proof of glucose lowering, 33 without required demonstration of efficacy on clinical outcomes. Aspirin for primary prevention of cardiovascular events in people with diabetes: A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Metformin, in the biguanide class, likely reduces blood glucose primarily by decreasing hepatic glucose 30 output and with some improvement in peripheral insulin sensitivity. In addition, metformin use is associated with modest weight reduction, favorable effects on lipid levels, decrease in inflammatory markers, improvement in coagulation profiles, and low risk for hypoglycemia. The effect on the primary composite outcome, including micro- and macrovascular complications, proved neutral. Concerns about the potential of metformin to cause lactic acidosis delayed its regulatory approval in the United States and hindered its clinical uptake, stemming from earlier observations with another biguanide, phenformin, that clearly caused lactic acidemia and was removed from the market on that basis. Despite widespread global use of metformin for more than five decades, however, and a substantial aggregated database of comparative clinical trials, no convincing signal for increased lactic acidemia 34,35 with metformin treatment has emerged. Given this absence of data supporting the concern for lactic acidosis with metformin, in 2006 the U. These changes should allow use of this effective, safe, and inexpensive medication to hundreds of thousands of patients in the United States alone. Metformin is the only oral antihyperglycemic medication routinely recommended to be continued in combination with insulin therapy. Sulfonylureas, in clinical use since 1950, are the oldest oral antihyperglycemic medications. Although sulfonylureas typically are well tolerated and are relatively potent, their use results in the highest rate of hypoglycemia of any available oral antihyperglycemic drug. This potential discrepancy between the apparent safety of sulfonylureas when studied in randomized trials versus their purported risk that emerges in observational studies has two leading explanations. First, the observational studies could be wrong, their findings influenced by confounders not assessable in the datasets, most importantly indication. Alternatively, under the careful observation of clinical trials the drugs could be safe, but their potential dangers may only emerge when used in the general practice setting. These data were considered hypothesis generating because of failure to meet the primary outcome. These data from a controversial meta-analysis of phase 2 and 3 data initially led to severe product label restrictions for use in the United States and to withdrawal of rosiglitazone from the market elsewhere. The rosiglitazone product label has since undergone updating to reflect this finding, but the drug remains infrequently used. Each of these is administered as a once-daily tablet, with modest glucose-lowering potency and with the clinical benefits of neutral effects on weight and low risk for hypoglycemia. They have variable effects on glucose metabolism that include the stimulation of glucose- dependent insulin secretion, suppression of glucagon (also in a glucose-dependent fashion), a slowing of gastric emptying, and satiety enhancement. They do not increase the risk of hypoglycemia unless used with other drugs that themselves increase the risk (e. It enrolled 7020 patients with longstanding diabetes (57% for >10 years) with mean follow-up of 3. These newer agents share the advantage of a very low risk for hypoglycemia, and many are weight-neutral or cause weight loss. In the insulin and sulfonylurea analyses, resulting in hemoglobin (Hb) A levels of 7. The initial trial observations persisted up to 17 months of follow-up in this 30 cohort, during which the primary composite outcome risks remained similar between groups. The risk of death from any cause was 19% higher in patients randomly assigned to the more intensive glucose control strategy in the trial (P < 0. The absence of randomization to specific therapies renders post hoc analysis of cause especially difficult. Patients randomly received either intensive glucose control with gliclazide plus other drugs in the intensive arm, compared with standard control with other drugs. An overriding consideration of such an approach is the limited evidence of short-term benefits from any reduction in microvascular disease in those with limited life expectancy. These observed upper confidence limits are well within the noninferiority margins recently adopted by U. Whether empagliflozin, liraglutide, semaglutide, or pioglitazone would prove effective in primary prevention remains unknown. Greater concerns regarding a particular domain are represented by increasing height of the corresponding ramp. Thus, characteristics/predicaments toward the left justify more stringent efforts to lower HbA1c, whereas those toward the right suggest (indeed, sometimes mandate) less stringent efforts. Where possible, such decisions should be made with the patient, reflecting his or her preferences, needs, and values. This “scale” is not designed to be applied rigidly but to be used as a broad construct to guide clinical decision making. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. The diagnosis of diabetes early in the hospital course is important because it influences later therapeutic decisions. These protocols typically targeted permissive hyperglycemia of 126 to 200 mg/dL during the infusion. Similar findings pertained to the subset of 4662 patients with diabetes at 68 study entry. In + addition, patients with diabetes should have serial monitoring of [K ], given the high prevalence of type 4 renal tubular acidosis in the diabetic population. Biologic effects that support the incremental efficacy of beta blockers in the setting of diabetes include the restoration of sympathovagal balance in diabetic patients with autonomic neuropathy and decreasing fatty acid metabolism within the myocardium, reducing myocardial oxygen demand. In the selection, one may consider the variable effects of available beta blockers on glycometabolic parameters, with favorable effects of some (e. Similarly, in analyses of diabetic subsets from randomized trials of thrombolytics, patients with diabetes derive greater absolute benefit from thrombolytic therapy than 62 nondiabetic patients. Current guidelines recommend medical treatment, including anti-ischemic drugs as first-line treatment of this patient population. For patients requiring revascularization, the optimal revascularization strategy remains controversial. Thus, careful evaluation of the general treatment indication and consideration of the optimal therapeutic strategy has particular importance in this high-risk population.

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In general order 4mg ondansetron treatment glaucoma, the more severe the presenting symptoms order ondansetron overnight delivery medications knowledge, the more aggressive are the evaluation and treatment order ondansetron 4mg with amex symptoms colon cancer. Loss of consciousness believed to be of cardiac origin typically mandates an exhaustive search for the etiology and may require invasive, device-based diagnostic evaluation and treatment. A family history of a significant cardiac arrhythmia may not directly inform the prognosis of a patient, but it should alert the practitioner to the possibility of a heritable trait that may increase susceptibility to development of an arrhythmia. Palpitations Palpitations are the awareness of the heartbeat that may be caused by a rapid heart rate, irregularities in heart rhythm, or an increase in the force of cardiac contraction, as occurs with a post–extrasystolic beat; however, this perception can also exist in the setting of a completely normal cardiac rhythm. Patients who complain of palpitations describe the sensation of an unpleasant awareness of a forceful, irregular, or rapid beating of the heart. The latter is particularly noteworthy because if untreated, it may be associated with stroke or may produce a tachycardia-induced cardiomyopathy. Patients may use terms such as a “pounding” or “flipping” sensation in the chest; a fullness or pounding in the throat, neck, or chest; or a pause in the heartbeat, or “skipped a beat. Usually, the premature beat, particularly if it is a ventricular extrasystole, occurs too early to permit sufficient ventricular filling to cause a sensation when the ventricle contracts. The ventricular systole that ends the compensatory pause is often responsible for the actual palpitation, the result of a more forceful contraction from prolonged ventricular filling or increased motion of the heart in the chest. Premature atrial or ventricular complexes constitute the most common causes of palpitations. If the premature complexes are frequent, or particularly if a sustained tachycardia is present, patients are more likely to have additional symptoms, such as lightheadedness, syncope or near-syncope, chest discomfort, fatigue, or shortness of breath. The context and symptoms associated with palpitations can be diagnostically and prognostically informative. However, even tachycardias that start abruptly can begin and end with extra beats appearing to have a more gradual onset and offset. The rate of an untreated tachycardia often narrows diagnostic possibilities, and patients should be taught to count their radial or carotid pulse rate, noting whether it is regular or irregular. Patients with bradyarrhythmias may have symptoms of low cardiac output, including fatigue, weakness, dizziness, dyspnea, and syncope (see Chapter 40). Palpitations can result from an increased force of contraction associated with longer ventricular filling times and may be prominent symptoms in bradycardias. Syncope, Presyncope, and Altered Level of Consciousness Syncope, commonly referred to as “fainting” or “passing out,” is a transient, self-limited loss of consciousness and posture resulting from a drop in blood pressure with cerebral hypoperfusion and should always prompt a search for a cause (see Chapter 43). It is important to distinguish syncope from other causes of transient loss of consciousness, such as seizures, metabolic disorders (hypoglycemia, hypoxia [e. The unheralded loss of consciousness in any patient, even if benign from the cardiac perspective, can be dangerous depending on the circumstances (e. When caused by a cardiac arrhythmia, the onset of syncope is rapid and the duration is brief, with or without preceding aura, and is not typically followed by a postictal confusional state. Palpitations preceding syncope may support an arrhythmic cause of syncope but are often absent if the loss of consciousness is rapid. Seizure activity is uncommon and occurs mostly after prolonged asystole or a rapid ventricular arrhythmia. Therefore, the seizure does not begin with or anticipate the syncope, whereas in epileptic seizures, convulsive movements start within seconds of the onset of syncope. In summary, syncope with early seizure activity is frequently caused by epilepsy, whereas later seizure activity is more likely caused by a cardiac arrhythmia with cerebral hypoperfusion. The history of syncope should be elicited and interpreted carefully, because older people who have fallen might deny loss of consciousness during the event because of retrograde amnesia. Bradycardia can follow tachycardia in patients with the bradycardia-tachycardia syndrome, and treatment of both may be necessary. Of the reflex syncopes—neurocardiogenic, carotid hypersensitivity, and situational—neurocardiogenic is the most common. It should be differentiated from syncope caused by orthostasis, which may be seen in 3 autonomic failure (e. Vasodepressor and cardioinhibitory syncope usually unfold more slowly and can be preceded by manifestations of autonomic hyperactivity such as nausea, abdominal cramping, diarrhea, sweating, or yawning. Palpitations and presyncope on standing can be symptoms of postural orthostatic tachycardia syndrome. Noncardiac causes of syncope, such as hypoglycemia, transient ischemic attack, and psychogenic causes, often can be excluded by a careful history (see Chapters 35 and 43). A variety of noncardiac conditions may be associated with life-threatening arrhythmias, including neurologic diseases (stroke, intracranial hemorrhage, epilepsy, neuromuscular disease, Parkinson disease), diabetes, obesity, cirrhosis, anorexia, and bulimia. Medications and recreational drugs can increase the risk of lethal arrhythmias; patients should be asked about use of antiarrhythmics, stimulants, decongestants, psychotropics, antibiotics, alcohol, amphetamines, cocaine, and supplements, especially those used for weight loss and energy enhancement. The absence of significant cardiopulmonary disease often, but not always, suggests benignity of a rhythm disturbance. In contrast, palpitations, syncope, or near-syncope in the setting of significant heart or lung disease have a more ominous prognosis. The general physical examination is also important and can identify medical conditions associated with cardiac manifestations and arrhythmias. Inspection of the skin may reveal erythema chronicum migrans, the rash associated with Lyme disease; hair loss and exophthalmos may reflect the presence of thyroid disease; and ptosis and skeletal muscle wasting or myotonia may indicate the presence of neuromuscular disease (see Chapter 97). The examiner first needs to listen carefully over both carotid arteries to be certain that no bruit is present, palpate lightly to determine that a normal carotid pulse is present, and then gently depress or rub the carotid sinus. A number of other studies, alone or in combination, may assist in the diagnosis and management of patients with cardiac arrhythmias. Cardiac Imaging The prognostic implications of a cardiac arrhythmia depend on context, most importantly the presence of structural heart disease. Cardiac imaging plays an important role in the detection and characterization of myocardial structural abnormalities that can render the heart more susceptible to arrhythmias. Echocardiography (see Chapter 14) is frequently employed to screen for disorders of cardiac structure and function. B, Two cardiac magnetic resonance images show evidence of delayed gadolinium enhancement in the midwall of the left ventricle (arrows). Short-term continuous Holter monitoring may be sufficient to adjudicate daily symptoms related to arrhythmias such as palpitations or presyncope, quantify a particular arrhythmia phenomenon (e. If the arrhythmia does not occur with sufficient frequency, 24-hour, or even 48-hour, recording is not likely to be useful. A longer-term monitoring system is required for arrhythmias that occur less frequently. The sensor wirelessly transmits collected data to a portable monitor that analyzes the rhythm data. If an arrhythmia is detected, the monitor automatically transmits recorded data wirelessly via the Internet to a central monitoring station for subsequent analysis. Newer, more compact systems have been developed that contain all the components in a wearable patch (eFig.

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Radiolucent foam bolsters purchase ondansetron in united states online treatment of hyperkalemia, pillows discount ondansetron 8 mg with amex medications ending in pril, wedges cheap ondansetron 8mg with visa symptoms neuropathy, and other assorted positioning aids are available commercially or can be produced from common radiolucent materials. These aids are helpful for comfortable and stable patient positioning especially when the patient is prone. Rotated or contorted patient postures will translate into diffculty patient or onto the fuoroscopy table itself prior to patient with subsequent image interpretation and may require awk- positioning (Fig. An image should then be obtained ward positioning angles for the C-arm, adding unnecessary and manipulated on the monitor so that the top of the image complexity to the procedure (Fig. This image orientation should scope up to the table and orient it into the neutral position over remain standard and should be checked and reestablished at the patient. The neutral position of the fuoroscope is defned the beginning of each day and after restarting the machine as the position at which all rotation axes are zero. As the injectionist gains experience working should be directly vertical with the image intensifer over the 10 Needle Manipulation Techniques 127 Fig. A scout image should be obtained and the image should be manipulated on the monitor until it is straight and square. For spinal procedures the patient’s spine should be oriented in the middle of the monitor screen so that the long axis of the spine is parallel with the vertical axis of the monitor (Fig. An initial image on the monitor that is straight and square allows the injectionist to begin from a position of familiarity. As the C-arm is moved during the procedure, the view on the fuoroscopic monitor will change. Starting with easily identifable anatomic landmarks viewed with standard orientation allows the injectionist to maintain an understanding of the anatomic landmarks as their fuoro- scopic appearance adjusts with changing fuoroscopy views. Especially with more complex procedures in severely degenerative spines, as the procedure progresses and the C-arm is moved into increasingly unfamiliar oblique angles with cephalad or caudad tilt, fuoroscopic anatomy may appear much less familiar and the injection- ist may become disoriented and lose an understanding of the fuoroscopic shadows that were previously identifed as known anatomic structures. In these diffcult cases, if a basic landmark such as move the image intensifer to the left and right edges of the the superior articulating process of a specifc spinal level table. If the skin insertion point is not properly chosen, were viewed in isolation, the injectionist may not be able to the injectionist will be “fighting against” this suboptimal identify any relevant anatomic landmarks. The simplest pro- Visualize the Target cedures are those such as an uncomplicated posterior interlaminar lumbar epidural steroid injection where an In order to successfully advance a needle through the skin unobstructed fluoroscopic view of the target can be and into a pain-generating target within the body, one should obtained readily and the needle can follow a straight line frst be able to visualize the path leading to the target with the to its destination. The fuoroscope reveals tissues of In comparison, a transforaminal L5/S1 epidural injec- varying densities which are represented by varying shades of tion is somewhat more diffcult because the target, which gray on the monitor screen. Once the needle tip penetrates is the base of the L5 pedicle at the 6 o’clock position, may the skin, it is of course no longer visible to the naked eye but not be directly visible with the fuoroscope. The practitioner procedure, the injectionist may be required to advance the must use the fuoroscopic images to visualize in the “mind’s needle down a long, narrow corridor extending from the eye” the relevant anatomy between the skin insertion point of skin insertion point to the target. The needle may have to the needle and the anatomical target in order to anticipate the initially move medial from the skin insertion point in various anatomic structures penetrated and bypassed by the order to avoid the ileum at an approximate depth of 2″, needle as it advances. Patients often do not forget painful experiences and will most assuredly tell friends, family, and the referring physician all about it. Conversely, a happy patient who has minimal discomfort during a procedure will sing the doctor’s praises. The liberal use of local anesthetic to lessen the pain of needle placement requires minimal time and effort and need not add signifcant risk to the procedure. Once the needle is advanced through the initial skin and subcutaneous wheal, the needle stylet can be removed so that small, incremental doses of local anesthetic can be injected as the needle is advanced further. It is sometimes advisable to advance the needle with the local anesthetic syringe attached in order to expedite local anesthetic injection. In more advanced proce- dures, such as percutaneous disc decompression where rela- tively large introducer needles are inserted, it is often advisable to use a 22 g or 25 g Quincke spinal needle to separately anesthetize a path to the target at the start of the Fig. In most therapeutic injections, it is certainly rea- sonable to use liberal amounts of local anesthetic to assure patient comfort. The toxic dose of 1% lidocaine without epi- cess at a depth of 3″, and then fnally move medial and nephrine is greater than 30 cc although far less volume will superior to the target at the pedicle base at a depth of 3. As a point of reference, an uncomplicated Advance the Needle in Small, Incremental interlaminar lumbar epidural injection in an anxious patient Fashion to the Target may require 5 cc of local anesthetic injected from the skin to the ligamentum favum in order to keep the patient comfort- Advancing needles in small, incremental steps to specifc tar- able during needle placement. With transforaminal epidural gets within the body is the essence of interventional pain injections near infamed nerve roots, additional small doses management. These small, incremental doses of local anesthetic near nerve roots usually create lit- tle sensory-motor impairment but may dramatically reduce Local Anesthesia discomfort. Almost all patients have fear and anxiety regard- The Art of Needle Placement ing spinal injections and many patients who are undergoing interventional pain procedures have experienced a high The art of safely and accurately placing needles into the degree of persistent pain leading up to the procedure. Prior to the advent of fuoroscopy in phase will go a long way toward alleviating preinjection the pain clinic, interventional pain practitioners relied solely anxiety, but this must be followed up by a procedure that is on contact with bony landmarks and the tactile feel of the minimally uncomfortable for the patient. For certain needle as it traversed various tissues in order to determine advanced procedures such as percutaneous disc decompres- needle tip location. This is the traditional approach of the sion or vertebroplasty, intravenous conscious sedation may anesthesiologist performing regional anesthesia. Schultz improve with experience and it may take hundreds of proce- quent spinal injection as the anatomy and physiology of dures before the injectionist is able to appreciate the subtle the spine began to be elucidated in the latter part of the differences in feel among various tissues. Leonard Corning performed experienced experts with advanced tactile skills, inaccurate the frst spinal anesthetic by accident on a dog when he needle placement is common when fuoroscopy is not used. Corning later anesthesiologists experienced in regional anesthesia have performed spinal anesthesia on humans and developed the determined that approximately one-third of needles were not frst beveled spinal needle in approximately 1890 [4]. For surgical Quincke and Bier furthered the science of spinal injection applications in the operating room, regional anesthesia is and spinal anesthesia with refnements on Corning’s nee- successful without fuoroscopy because large amounts of dle design near the end of the nineteenth century [5]. In pain management applications, however, fuoro- The spinal needles commonly used in interventional pain scopic guidance must be combined with regional anesthesia management have either Quincke or Tuohy-type bevels techniques in order to accurately target pain generators with diameter sizes ranging from 18 to 25 gauge and which are typically small anatomic structures confned to lengths ranging from 3″ to 7″ [7]. Since the feel of tissue transmitted from the needle tip to the fngers is equally important to fuoroscopic tracking of the History of Spinal Needles needle tip, it is important that the injectionist develop “edu- cated fngers” with respect to the feel of various tissue densi- Physician Alexander Wood of Edinburgh, England, is ties that are traversed by the needle tip during advancement. The hollow needle sets the stage for subse- vidual’s inherent tactile sensitivity. Place the needle into the superfcial aspect of the acteristic feel to the experienced spinal injectionist and that orange peel and then advance the needle incrementally the ligamentum favum will create a consistent resistance to through the various “tissue densities” of the orange. The peel the injection of air through the syringe, whereas the loose will have a different feel from the pulp, which will in turn tissues of the epidural space will offer no resistance to injec- feel different from the fbrous bands separating the various tion of air. Next, apply a plastic loss-of-resistance syringe loss-of-resistance technique, advancing a needle into the flled with air to the needle hub and advance the needle tip posterior midline is usually safe as long as the injectionist through the various layer densities while intermittently continues to feel frm resistance on the syringe plunger. Appreciate the way tissues Provided the needle lumen is not clogged with tissue debris, of varying densities provide varying degrees of “bounce” on the presence of frm resistance provides assurance that the the syringe plunger. Similarly, in humans, the subcutaneous needle tip is embedded in frm posterior spinal ligamentous tissue compartment will have a different feel from the fbrous tissue and has not entered the epidural or intrathecal spaces. Tissue feel and loss-of-resistance is The experienced injectionist gains information about best appreciated with the use of an air-flled syringe con- needle tip position by identifying the different feel of the nected to a Tuohy-type spinal needle of 22 gauge or greater. Although tactile feel alone is frequently inadequate to tance from tissues to such a degree that the injectionist can- place needles with consistent accuracy, the combination of not appreciate the different tissue layers. The use of a tactile feel with fuoroscopy allows the injectionist to be water-flled glass syringe was commonplace during the era consistently accurate with needle tip position before injec- of “blind epidural” injections performed without fuoros- tion. Contact of the needle tip with bone is unmistakable, copy, but the use of air-flled plastic syringes is now gener- and if the bone is accurately identifed and the anatomy ally accepted as providing superior tissue feel.

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This current is activated by the action 2+ potential–evoked intracellular Ca transient cheap 4 mg ondansetron with visa treatment 4 syphilis. Therefore cheap ondansetron 8mg on line medicine knowledge, interventions that augment the amplitude of the 2+ Ca transient associated with the twitch (e 8 mg ondansetron overnight delivery treatment diffusion. It is not currently known whether human cardiac myocytes express Ca -activated chloride channels. Sometimes, a transient depolarization follows phase 1 repolarization altering the initial voltage of the plateau (see eFig. During the plateau phase, which may last several hundred milliseconds, membrane conductance of all ions falls to rather low values; this is a time of high membrane resistance. Less change in current is required near plateau voltages than near resting potential levels to produce the same changes in transmembrane potential. This fast inactivation mechanism is sensitive to + changes in extracellular K in the physiologic range, with inactivation being more accentuated at low + extracellular K concentrations. Other ionic mechanisms that control plateau potential and duration include the 2+ 2+ kinetics of inactivation of the L-type Ca current. Reduced efficiency of intracellular free Ca in 2+ inducing Ca -dependent inactivation, such as in myocytes from hypertrophic hearts, can result in delayed repolarization. A nonselective, swelling- induced cation current has been shown to cause prolongation of action potentials in myocytes from failing 1 ventricles. The net membrane current becomes more outward, and the membrane potential moves to the resting 2+ + potential. A reduction in the outward potassium current through open inwardly rectifying + K channels renders the failing cardiomyocyte more susceptible to the induction of delayed 2+ afterdepolarizations triggered by spontaneous intracellular Ca -release events and therefore plays a 1 major role in arrhythmogenesis in the failing heart. Under normal conditions, the membrane potential of atrial and ventricular muscle cells remains steady + throughout diastole. The property possessed by spontaneously discharging cells is called phase 4 diastolic depolarization, which leads to initiation of action potentials resulting in automaticity. Sympathetic stimulation increases the rate of diastolic depolarization and shifts the maximum diastolic potential to a less negative 2+ value, thereby accelerating action potential firing. Arrows in the confocal image show the local Ca release in the submembrane space during late diastolic depolarization that precedes the rapid upstroke of the action potential. C, Model of sinoatrial node + 2+ cell pacemaking, as suggested by Maltsev and coworkers. The emergence of a general theory of the initiation and strength of the heartbeat. In a surface + membrane delimited series of events, depolarization-induced activation of the delayed rectifier K current I leads to membrane hyperpolarization, which is followed by slow diastolic depolarization viaK activation of a number of inward currents, including I and If CaT (see Table 34. A, Isochronal map of atrial activation during sinus rhythm superimposed on a photograph of the endocardial surface of the sinoatrial node region. The number on each isochronal line indicates the time of activation in milliseconds. B, Vm (blue) and Ca (i red) recordings from the superior (a), middle (b), and inferior (c) sinoatrial node, and right atrium (d). Note the presence of slow diastolic depolarization in the Vi m tracings a through c, but not in d. Intracellular calcium dynamics and acceleration of sinus rhythm by β-adrenergic stimulation. If the pacemaker site remains the same, alterations in the slope of the diastolic depolarization, maximum diastolic potential, or threshold potential can speed or slow the discharge rate. For example, if the slope of diastolic depolarization steepens, and if the resting membrane potential becomes less negative or the threshold potential more negative (within limits), the discharge rate increases (e. The same mechanism reduces input resistance at diastolic potentials, which means that a greater depolarizing current would be required to achieve the “threshold” for firing an action potential. Passive membrane properties, including membrane resistance, capacitance, and cable properties, play an important role in cardiac electrophysiology. Although the cardiac cell membrane is resistant to current flow, it also has capacitive properties, which means that it behaves like a battery and can store charges of opposite signs on its two sides—an excess of negative charges inside the membrane balanced by equivalent positive charges outside the membrane. These resistive and capacitive properties cause the membrane to take a certain amount of time to respond to an applied stimulus, rather than responding instantly, because the charges across the capacitive membrane must be altered first. A subthreshold rectangular current pulse applied to the membrane produces a slowly rising and decaying change in membrane voltage rather than a rectangular voltage change. A value called the time constant of the membrane reflects its capacitive property. The time constant tau (τ) is equal to the product of membrane resistance (R ) and cell capacitance (C ):m m This is the time taken by the membrane voltage to reach 63% of its final value after application of a steady current. The time course of changes in membrane potential after the application of a hyperpolarizing or depolarizing subthreshold current step is typically monoexponential in all myocyte types, thus indicating that the entire sarcolemma (including the T-tubular membrane; see eFig. Constitutive intracellular Na excess in Purkinje cells+ V promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia. When current is injected at a point, most of it flows parallel to the long axis inside the cell, but some leaks out. Because of this loss of current, the change in voltage of a cell at a site distant from the point of applied current is less than the change in membrane voltage at the point where the stimulus was applied. A measure of this property of a cable is called the space or length constant lambda (λ), which is the distance along the cable from the point of stimulation at which the voltage at steady state is 1/e (37%) of its value at the point of stimulation. Because the current loop in any circuit must be closed, current must flow back to its point of origin. Local circuit currents pass across gap junctions between cells and exit across the sarcolemmal membrane + to close the loop and complete the circuit. Inward excitation currents in one area (carried by Na in most + regions) flow intracellularly along the length of the tissue (carried mostly by K ), escape across the membrane, and flow extracellularly in a longitudinal direction. Through these local circuit currents, the transmembrane potential of each cell influences the transmembrane potential of its neighbor, because of the passive flow of current from one segment of the fiber to another across the low-resistance gap junctions (see Gap Junction Channels and Intercalated Discs and Fig. The speed of conduction in cardiac tissue depends on active membrane properties such as the + magnitude of the Na current, a measure of which is V̇max. Passive membrane properties also contribute to conduction velocity and include the excitability threshold, which influences the capability of cells adjacent to the one that has been discharged to reach threshold; the intracellular resistance of the cell, determined by free ions in the cytoplasm; the resistance of the gap junction; and the cross-sectional area of the cell. The direction of propagation is crucial because of the influence of anisotropy, in which conduction is faster parallel to the fiber axis compared to that across fibers. Loss of Membrane Potential and Development of Arrhythmias Many acquired abnormalities of cardiac muscle or specialized fibers that result in arrhythmias produce a loss of the resting membrane potential (less negative). This change should be viewed as a symptom of an underlying abnormality, analogous to fever or jaundice, rather than as a diagnosis in and of itself, because both the ionic changes resulting in cellular depolarization and the more fundamental biochemical or metabolic abnormalities responsible for the ionic alterations probably have a number of causative factors. For + + example, acute myocardial ischemia results in decreased [K ] and increased [K ] , release ofi o 2+ 2+ norepinephrine, and acidosis, which may be related to an increase in intracellular Ca and Ca -induced transient inward currents and accumulation of amphipathic lipid metabolites and oxygen free radicals. All these changes can contribute to the development of an abnormal electrophysiologic environment and arrhythmias during ischemia and reperfusion.