Radionuclide imaging tools for understanding arrhythmia mechanisms

Journal of Electrocardiology Vol. 27 Supplement

Interventional Electrophysiology State-of-the-Art and Future Directions

Michael D. Lesh, MD

complications, PSVT represents a small proportion of patients with arrhythmias. For ablation to continue its revolutionary effect, two arrhythmias must be addressed: ventricular tachycardia (VT) in the setting of healed infarction and atrial fibrillation. For both, new tools tailored to the task will need to be developed. For ablation of VT, better mapping devices are under development, including multielectrode basket catheters for simultaneous recording throughout the ventricle. Such a device will be mandatory for patients with hemodynamically unstable VT and/or multiple morphologies. More intelligent mapping systems will be needed to keep track of and help to interpret this volume of information. The use of quantitative body surface potential mapping along with multisite endocardial recording will need to be explored. For atrial fibrillation, the ability to simulate the maze operation, or its variants, using catheter techniques would be a tremendous advance, even if only a percentage of patients with atrial fibrillation could be cured without needing antiarrhythmic drugs.

Cardiac electrophysiology is the fastest growing field of inquiry within cardiovascular medicine and is quickly emerging as a subspecialty of its own, with an independent training path and board certification. The growth in this field is being generated by dramatic improvement in the safety and efficacy of nonpharmacologic therapy for cardiac arrhythmias, specifically catheter ablation and implanted devices for antitachycardia pacing, cardioversion, and defibrillation. Approximately 20,000 radiofrequency catheter ablations per year are performed in the United States. Most commonly, the indication is paroxysmal supraventricular tachycardia (PSVT). Although ablation is curative in more than 95% of cases, produces a dramatic improvement in quality of life, and is associated with a low incidence of From the University of California-San Francisco, San Francisco, California. Reprint requests: Michael D. Lesh, MD, University of CaliforniaSan Francisco, 500 Parnassus Avenue, Box 1354, San Francisco, CA 94143-1354.

Radionuclide Imaging Tools for Understanding Arrhythmia Mechanisms

Michael

W. Dae,

MD,

and

More than 300,000, sudden cardiac deaths occur each year in the United States, accounting for 50% of all cardiac-

Michael

D. Lesh,

MD

related mortality.X Most of these deaths occur in patients with prior healed myocardial infarctions and left ventricular dysfunction. 2 These deaths are thought to originate as ventricular tachycardia, which may degenerate into ventricular fibrillation. In most instances, there is no associated evidence for either acute infarction or significant ischemia. 2 Arrhythmia and sudden death are also important

From the University of California-San Francisco, San Francisco, California. Reprint requests: Michael Dae, MD, University of CaliforniaSan Francisco, 500 Parnassus Avenue, Box 1354, San Francisco, CA 94143-1L354.

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Journal of Electrocardiology Vol. 27 Supplement

features of noncoronary cardiomyopathy and heart failure. Approximately 40% of patients with severe heart failure die suddenly, presumably of arrhythmia. 3 The incidence of sudden death has been shown to correlate directly with both the extent of myocardial damage after infarction and the presence of complex spontaneous ventricular ectopy. 4,5 Also, compelling evidence has emerged that implicates the sympathetic nervous system in the genesis of ventricular arrhythmias and sudden death. Beta-blocker therapy has been shown to reduce the incidence of total and sudden death in patients with myocardial infarction. 6 Beta-blockers have been found to be particularly useful in decreasing the incidence of sudden death in patients with myocardial infarction and left ventricular dysfunction. 7 Elevated plasma catecholamines have been shown to identify patients with heart failure who are also at risk for sudden death, s Recent data showed significantly greater activation of myocardial sympathetic nerves in patients with left ventricular dysfunction and life-threatening ventricular arrhythmias compared with age-matched control subjects without a history of arrhythmia. 9

Scintigraphic Assessment of Myocardial Innervation The largest source of catecholamines is found in the sympathetic nerves of the heart, which are distributed on a regional basis. ~° Only in the past few years has it been possible to evaluate abnormalities in heart innervation in the intact animal. Recent developments in cardiac imaging have led to the ability to map the distribution of the sympathetic nerves in vivo. As a result, the pathophysiologic mechanisms relating alterations in sympathetic nerve activity to disease processes are now being explored. Myocardial sympathetic nerves have been shown to take up exogenously administered catecholamines. Early studies in rat hearts showed rapid accumulation of titrated norepinephrine (NE). n The labeled compound was subsequently shown to enter the sympathetic nerve endings by a high-affinity uptake process (uptake I); however, a lowaffinity, high-capacity nonneuronal uptake process was also found (uptake 2). 12 Subsequent studies showed that the neuronally bound catecholamine was retained in storage vesicles for long periods of time, whereas the nonneuronally bound compound was rapidly fnetabolized and subsequently washed out of the heart at a fairly rapid rate. ~3 Many other substances with chemical structures similar to NE were also shown to enter sympathetic nerves (false adrenergic transmitters ) . x4 Several years ago, metaiodobenzylguanidine (MIBG), an analog of the false adrenergic transmitter guanethidine, was developed. ~5 Radioiodonated MIBG was shown to localize to the heart and other organs in several animal species and in humans. ~6 Metaiodobenzylguanidine is thought to share similar uptake and storage mechanisms as NE, x7'18 but is not metabolized by monoamine oxidase or catechol-o-methyl transferase. Sisson et al. ~9 proposed another mechanism

for MIBG uptake related to passive diffusion into intact neurons. The existence of the passive neuronal uptake mechanism has not been confirmed, however. Many studies have evaluated the characteristics of MIBG uptake and distribution in experimental models designed to alter global and regional function of myocardial sympathetic nerves. In all instances, either global or regional sympathetic denervation has led to decreased uptake of MIBG.2O,21

Experimental Observations Global Myocardial Uptake We studied the uptake and washout of MIBG in globally denervated canine and h u m a n hearts. 22 We studied dogs at baseline and 1 week after the intravenous injection of 50 mg/kg 6-OH dopamine, used to create a chemical sympathectomy. Images were acquired at 5 minutes 3 hours after injection of ~23IMIBG At baseline, there was homogeneous myocardial uptake of MIBG on initial images, with homogeneous retention of MIBG at 3 hours. All the globally denervated canine hearts showed homogeneous uptake of MIBG initially but near-complete washout of MIBG at 3 hours. These results suggest that the initial accumulation of MIBG in the denervated canine heart represents non-neuronal localization and support the conclusion that MIBG localization on the delayed images in the normally innervated hearts represents accumulation in sympathetic nerve endings. Humans were studied a mean of 3 months after cardiac transplantation. We found no evidence of MIBG localization in the transplanted h u m a n heart on either the early or delayed images. These unexpected findings suggest that nonneuronal uptake is not significant in human hearts, unlike other species. Acute changes in adrenergic nerve activity of the heart have been assessed by measuring the rates of loss of neuronally bound MIBG. Sisson et al? 3 compared the rates of loss of NE and MIBG in rat and canine hearts. They used yohimbine, an alpha-2 adrenoreceptor antagonist, to increase the function of the sympathetic nerves and clonidine, an alpha-2 agonist, to decrease the activity of the sympathetic nerves. In rat hearts, yohimbine induced similar increases in rates of loss of 3H-NE and 125I MIBG, whereas clonidine induced similar decreases in rates of loss of 3H-NE and 125I MIBG. Imaging studies in canine hearts with ~23I MIBG showed similar responses to yohimbine and clonidine. These results suggest that it may be possible to assess acute changes in sympathetic tone noninvasively.

Regional Myocardial Uptake We also evaluated the ability of MIBG to detect regional denervation in canine hearts. 2~ Metaiodobenzylguanidine was used to image the distribution of sympathetic nerves,

Radionuclide Imaging Tools forArrhythmia whereas thallium-201 was used to image myocardial perfusion (myocytes). We compared the distribution of 1231 MIBG to thallium-201 in dogs that underwent prior left or right stellectomy or applications of phenol to the epicardial surface. These regionally denervated hearts showed appropriately reduced uptake of MIBG relative to thallium in the posterior left ventricle in left stellectomized hearts and in the anterior left ventricle in right stellectomized hearts (Fig. 1). Phenol-treated hearts showed reduced MIBG uptake within and beyond the region of phenol application. Control hearts showed similar and homogeneous distributions of MIBG and thallium. There was a significant decrease in tissue NE content in areas showing reduced MIBG uptake versus areas showing normal MIBG uptake, confirming regional denervation. In another series of experiments, we evaluated the contractile responses of hearts showing regional denervation by MIBG imaging. 24 Regional denervation was produced by epicardial phenol treatment. Regions showing normal MIBG uptake showed enhanced contractile responses during stellate stimulation, after infusion of tyramine, and after isoproterenol iniusion. Regions showing reduced MIBG uptake showed :no augmentation in the contractile response during stellate stimulation or infusion of tyramine, confirming deneJTvation. There was, however, an increased contractile response to isoproterenol infusion, indicating intact postsynaptic responses to beta-receptor stimulation. We assessed MIBG uptake in dogs with transmural and nontransmural myocardial infarction. 25 Transmural myocardial infarction was produced by the injection of vinyl latex into the left anteriior descending coronary artery, and nontransmural myocardial infarction was produced by ligation of l~he left anterior descending coronary artery. Hearts with transmural infarction showed zones of absent MIBG and thallium, indicating scar. Adjacent and distal

Fig. 1. Color functional maps of myocardial slices from a dog with left and right stellectomy. The red area represents a balanced distribution of MIBG and thallium (normal innervation), while the yellow to green area represents reduced MIBG relative to thallium (regional denervation). From Dae et al. 21 With permission.

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regions showed reduced MIBG but normal thallium uptake, indicating viable but denervated myocardium. Denervation was confirmed by reduced tissue NE content and absent histofluorescence of sympathetic nerves at microscopy. Nontransmural myocardial infarction also showed regional denervation. There were zones of wall thinning with decreased thallium uptake and a greater reduction of MIBG localized to the region of the infarct. These findings demonstrate that in experimental myocardial infarction, the relative uptake of MIBG shows a spectrum: no uptake in the center of an infarct with no flow and relative decreased MIBG uptake in the border zone of an infarct. This border zone may be transmural or nontransmural. These results confirmed previous reports that transmural myocardial infarction can lead to denervation 26 and introduced the concept that nontransmural infarction could result in denervation as well, probably due to regional ischemic damage to sympathetic nerve endings. We further evaluated the hypothesis that severe transient ischemia could produce chronic injury to sympathetic nerves. We studied dogs 7 - 1 0 days after a transient 2-hour closed-chest balloon occlusion of the left anterior descending coronary artery. Ten of 11 dogs showed evidence of ischemia during the acute intervention and developed nonsustained ventricular tachycardia during reperfusion. All infarctions were nontransmural. Five dogs showed scintigraphic denervation in normally perfused myocardium overlying necrotic subendocardium. There was a larger extent of denervation than scar (25.5 vs 8.2%, P < .02). Six dogs showed no evidence of denervation and had minimal subendocardial scar. These results confirmed that denervation can occur in ischemic myocardium in the absence of transmural scar or trauma to the nerves with external manipulation of coronary arteries. The presence of transient ischemia did not predict the development of chronic denervation. However, the severity of ischemia, as determined by the extent of related necrosis, did correlate with the development of chronic denervation. We assessed the effects of increased efferent sympathetic activity on the epicardial action potential duration in dogs with chronic myocardial infarction and regional denervation 27 (Fig. 2). The monophasic action potential was recorded from a mean of 11 epicardial sites before and after stellate ganglion stimulation. Recording sites were identified as either innervated or denervated from MIBG/thallium functional maps of myocardial slices. In the absence of stellate stimulation, there were no differences in action potential duration between innervated and denervated regions (Fig. 3). However, during stellate stimulation, innervated areas showed a significant shortening of action potential duration, whereas denervated areas showed no significant change in action potential duration (Fig. 3). These findings confirm the fact that regional denervation can lead to heterogeneity of electrophysiologic responses and suggest that increased dispersion of refractoriness may occur during states of increased sympathetic tone. In a recent preliminary study, we tested the hypothesis that electrical body surface potential mapping could detect and localize regional dispersion of refractoriness caused by sympathetic denervation. 28 We applied phenol to the

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Journal of Electrocardiology Vol. 27 Supplement greater right-sided negativity (20.5 + 7.3 vs 9.6 + 5.8%, P = .01) and greater left-sided positivity (98.5 ___ 1.8 vs 92.9 + 6.2%, P = .01). The gradient significantly increased after phenol ( 134 + 27 mvms to 246 + 115 mvms, P = .03). In these preliminary studies, QRST isoarea body surface potential maps showed consistent changes with regional denervation.

Clinical Studies of MIBG Uptake Fig. 2. Scintigraphic color functional map from a dog with patchy anterior wall infarction (5.8% total heart weight). Heart slices are cut from apex to base with anterior downward. Areas of yellow and green represent regional denervation in the area of infarction. From Newman et al. 2~ With permission. epicardial surface of eight dogs to create regional denervation. Body surface potential maps using 64 leads were acquired from the anterior thorax, at constant heart rates, before and 1 week after phenol application. Sympathetic denervation was confirmed by MIBG and thallium imaging. The areas of negativity and positivity on the right and left body surfaces were calculated from QRST isoarea body surface maps. Also, the gradient was calculated between peak maxima and peak minima on the maps. The MIBG imaging showed denervafion in the anterior left ventricle corresponding to the phenol painted ares. The mean extent of denervation was 36 -- 7%. The mean severity of denervation was 0.46 -- 0.04, representing the fractional reduction of MIBG uptake compared with the normal region. The body surface potential maps after phenol showed

Fig, 3. Examples of recordings obtained from two areas taken from one slice (second from apex), illustrated in Figure 2. Innervated posterior (right panel) and denervated anterior (left panel) were examined. During sympathetic stimulation, APDso and APD9o shorten minimally from baseline in the denervated areas and shorten significantly in the innervated area. Note that blood pressure rose at both times and that the ECG does not change during sympathetic stimulation. All recordings were made during continuous right ventricular pacing at 300 ms. From Newman et a l . 27 With permission.

Several studies have examined the kinetics of MIBG washout in various patient populations. Patients with generalized autonomic neuropathy, 29 generalized adrenergic dysfunction, 3° dilated cardiomyopathy, 31 and severe hypertrophic cardiomyopathy 32 have all shown enhanced washout of MIBG from the heart. Whether this enhanced washout is due to denervation and failure of retention of MIBG or to enhanced sympathetic activity is not known. The sympathetic nervous system has long been observed to play a major role in the pathogenesis of congestive heart failure. 33 Recent studies have examined MIBG uptake and washout in patients with heart failure. Henderson et al.31 showed enhanced washout and increased heterogeneity of MIBG localization in patients with dilated cardiomyopathy. Glowniak et al. 34 also showed abnormalities in MIBG localization in dilated cardiomyopathy. Schofer et al. 35 found a significant correlation between reduced MIBG uptake and reduced myocardial NE content and ejection fraction in patients with idiopathic dilated cardiomyopathy. Merlet et al. 36 recently reported the results of a prospective study of a group of 90 patients with congestive heart failure related to idiopathic dilated cardiomyopathy. They assessed MIBG uptake, ejection fraction, cardiothoracic ratio

Dog 116 Slice 216 VENTRICULAR PACING AT CL 300msec Site 10 Normal Innervation and Perfusion

Site 9 Denervation with Perfusion

II ~

II

100rnmHg~_ FAP

oJ

Baseline APDso = 195rose© APDso= 125msec

Stellate stimulation APDso = 20Omsec APDso= t 30mse©

Baseline APDSO= 235msec APDso = =OOmsec

Stellate stimulation APDso : 2 lOmsec APDso= 17Omle¢

Radionuclide Imaging Tools for Arrhythmia on x-ray, and M-mode echocardiographic data and followed the patients up to 27 months. Multivariate life-table analysis showed that MIBG uptake, as assessed by the myocardial-.to-mediastinal count ratio on anterior planar MIBG scans at 4 hours after injection, was the best predictor for survival. These exciting results may have a significant effect on the assessment of prognosis in patients with heart failure. Further studies are needed. Several recent studies have reported abnormal regional distribution of MIBG uptake in clinical conditions related to increased arrhythmogenesis, including myocardial infarction, 37 long QT syndrome, 3a patients with ventricular tachycardia in the absence of coronary disease, 30 and patients with arrhythmogenic right ventricular cardiomyopathy. 4°

Conclusion An increasing body of literature confirms the feasibility of imaging the sympathetic innervation of the intact heart. Early studies suggest that the many hypotheses relating enhanced autonomic tone and autonomic imbalance to increased rJLskof arrhythmia and sudden death can be successfully tested. Future studies to compare functional abnormalities of the sympathetic nerves to myocardial perfusion, metabolism, adrenergic receptor density, and signal transduction may provide a more comprehensive understanding of the action of the autonomic nervous system in disease states. The ability to detect the distribution of innervation scintigraphically and to correlate these image findings with electrophysiologic assessment of vulnerability may provide an important new understanding of the interaction of the sympathetic nerves with cardiac pathophysiology. Also, imaging may provide a noninvasive means to detect patients at risk for sudden death and possibly provide a basis for a more rational approach to therapy.

Fieferences 1. Myerburg R, Kess][er K, Castellanos A: Sudden cardiac death: structure, function, and time-dependence of risk. Circulation 85:I-2, 1992 2. Hurwitz J, Josephson M: Sudden cardiac death in patients with chronic coronary heart disease. Circulation 85:I-43, 1992 3. Francis G: Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence, and prognosis. Am J Cardiol 57:3B, I986 4. Follansbe W, Michelson E, Morganroth J: Nonsustained ventricular tachycardia in ambulatory patients: characteristics and association with sudden cardiac d e a t h Ann Interu Med 92:741, 1980 •5. Gang F, Bigger J, Livelli F: A model of chronic arrhythrajas: the relationship between electrically inducible ventricular tachycardia, ventricular fibrillation threshold, and myocardial infarct size. Am J Cardiol 50:469, 1982

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6. Yusuf S, Peto R, Lewis J et al: Beta-blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 25:335, 1985 7. Chadda K, Goldstein S, Byington R, Curb J: Effect of propranalol after acute myocardial infarction in patients with congestive heart failure. Circulation 73: 5O3, 1986 8. Cohn J, Levine T, Olivari M e t al: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311:819, 1984 9. Meredith I, Broughton A, Jennings G, Esler M: Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med 325:618, 1991 10. Randall WC: Nervous control of cardiovascular function. Oxford University Press, New York, 1984 11. Whitby L, Axelrod J, Weil-Malherbe H: The fate of 3H-norephinephrine in animals. J Pharmacol Exp Ther 132:193, 1961 12. Iversen LL: Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 41:57 I, 1971 13. Lightman SL, Iversen LL: The role of uptake in the extraneuronal metabolism of catecholamines in the isolated rat heart. Br J Pharmacol 37:638, 1969 I4. Kopin I: False adrenergic transmitters. Annu Rev Pharmacol 8:377, 1968 I5. Wieland K, Wu J, Brown L et al: Radiolabeled adrenergic neuron-blocking agents: adrenomedullary imaging with (131 I) iodobenzylguanidine. J Nucl Med 21: 349, 1980 16. Kline RC, Swanson DP, Wieland DM et al: Myocardial imaging in man with I-123 inedaiodobenzylguanidine. J Nucl Med 22:129, 1981 17. Manger WM, Hoffman BB: Heart imaging in the diagnosis of pheochromocytoma and assessment of catecholamine uptake-teaching editorial. J Nucl Med 24: 1194, 1983 18. Wieland DM, Brown LE, Rogers WL et al: Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med 22:22, 1981 I9. Sisson JC, Wieland DM, Sherman P e t al: Metaiodobenzylguanidine as an index of the adrenergic nervous system integrity and function. J Nucl Med 28:1620, 1987 20. Sisson JC, Lynch J J, Johnson J e t al: Scintigraphic detection of regional disruption of adrenergic neurons in the heart. Am Heart J 116:67, 1988 21. Dae MW, O'Connell JW, Botvinick EH et al: Scintigraphic assessment of regional cardiac adrenergic innervation. Circulation 79:634, 1989 22. Dae M, De Marco T, Botvinick E et al: Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts: implicati.ons for clinical studies. J Nucl Med 33:1444, 1992 23. Sisson J, Bolgas G, Johnson J: Measuring acute changes in adrenergic nerve activity of the heart in the living animal. Am Heart J 12I:1119, 1991 24. Mori J, Pisasri T, Oldea G e t al: Usefulness and limita-

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tions of regional cardiac sympathectomy by phenol. Am J Physiol 26:H1523, 1989 Dae M, Herre J, Botvinich E et al: Assessment of adrenergic innervation after transmural versus nontransmural myocardial infarction. J Am Coil Cardiol 17:1416, 1991 Barber M, Mueller T, Henry D et al: Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium. Circulation 67:787, 1983 Newman D, Munoz L, Chin M e t al: The effects of canine myocardial infarction on sympathetic efferent neuronal function: scintigraphic and electrophysiologic correlates. Am Heart J 126:1275, 1993 Stanely M, Grogin H, Chin MI et al: Body surface mapping detects regional sympathetic imbalance in canine ventricular myocardium. J Am Coll Cardiol 21 (Suppl):53A, 1993 Sisson JC, Shapiro B, Meyers Let al: Metaiodobenzylguanidine to map scintigraphically the adrenergic nervous system in man. J Nucl Med 28:1625, 1987 Nakajo M, Shimabukuro K, Miyji N: Rapid clearance of iodine-131 M1BG from the heart and liver of patients with adrenergic dysfunction and pheochromocytoma. J Nucl Med 26:357, 1985 Henderson EB, Kahn JK, Corbett JB et al: Abnormal 1-123 metaidobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive myocardiomyopathy. Circulation 78:1192, 1988 Taki J, Nakajima K, Bunko Het al: Whole-body distribution of iodine 123 metaiodobenzylguanidine in hypertrophic cardiomyopathy: significance of its washout from the heart. Eur J Nucl Med 17:264, 1990

33. Hasking G, Eslen M, Jennings Get al: Norepinephrine spillover to plasma in patients w i t h congestive heart failure: evidence of increased overall and cardiotenal sympathetic nervous activity. Circulation 73:615, 1986 34. Glownaik JV, Turner FE, Gray LL et ah Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants. J Nud Med 30:1182, 1989 35. Schofer J, Spielmann R, Schuchert A et al: Iodine- 123 metaiodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 12:252, 1988 36. Merlet P, Valette H, Dubois R etah Prognostic valve of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med 33:471, 1992 37. Stanton MS, Tuli MM, Radtke NL et al: Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using 1-123-metaiodobenzylguanidine. J Am Coll Cardiol 14:1519, 1989 38. Gohl K, Feistel H, Weikl A et al: Congenital myocardial sympathetic dysinnervation: a structural defect of idiopaghic long QT syndrome. PACE 14:1544, 1991 39. Mitrani R, Klein L, Miles W e t al: Regional cardiac sympathetic denervation in patients with ventricular tachycardia in the absence of coronary artery disease. J Am Coil Cardiol 22:1344, 1993 40. Wichter T, Hindricks G, Lerch H et al: Regional myocardial sympathetic dysinnervation in arrhythmogenic right ventricular cardiomyopathy. Circulation 89:667, 1994

Considerations in the Design and Implementation of Computerized EP Laboratory Systems M a t t h e w W. Prucka

With the increased sophistication of electrophysiology (EP) procedures, it has become necessary to improve the capability of recording and analysis systems. New EP techniques have created a need to record data from many channels in multiple configurations. Large amounts of data From Prucka Engineering, Houston, Texas.

Reprint requests: Matthew W. Prucka, Prucka Engineering, 8022 El Rio, Houston, TX 77054.

must be acquired, stored, and analyzed during these studies. Analog systems can no longer meet the massive data requirements of today's EP cases; therefore, computerized systems are needed to assist in acquisition, analysis, and organization of this information. When designing such a system for commercial availability, a set of achievable design goals must be set. To be well received in the market and to serve EPs well, the systems that we design must meet our goals of flexibility, useability,