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Romano-Ward syndrome

Romano-Ward syndrome, is the major variant of long QT syndrome. It is a condition that causes a disruption of the heart's normal rhythm. more...

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This disorder is a form of long QT syndrome, which is a heart condition that causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats can lead to fainting, seizures, or sudden death.

Romano-Ward syndrome in inherited in a autosomal dominant pattern. It is the most common form of inherited long QT syndrome, affecting an estimated 1 in 5,000 people worldwide, although more people may be affected but never experience any signs or symptoms of the condition.

Mutations in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes cause Romano-Ward syndrome. The proteins made by most of these genes form channels that transport positively-charged atoms, such as potassium and sodium, in and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in any of these genes alter the structure or function of channels, which changes the flow of ions between cells. A disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of Romano-Ward syndrome.

Unlike most genes related to Romano-Ward syndrome, the ANK2 gene does not produce an ion channel. The protein made by the ANK2 gene ensures that other protein, particularly ion channels, are inserted into the cell membrane appropriately. A mutation in the ANK2 gene likely alters the flow of ions between cells in the heart, which disrupts the heart's normal rhythm and results in the features of Romano-Ward syndrome.

This article incorporates public domain text from The U.S. National Library of Medicine


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Head-upright tilt test: a new method of evaluating syncope
From American Family Physician, 1/1/93 by Douglas A. Wolfe

Syncope is defined as a sudden, transient loss of consciousness associated with the inability to maintain postural tone. In as many as 50 percent of cases, syncope defies diagnosis.[1-5] This article discusses a relatively new diagnostic tool, the head-upright tilt test, and its use in the evaluation of patients with syncope.

Scope and Impact of Syncope

Each year, 300,000 patients present to emergency departments because of syncope.[1-3,6] An equal number of patients are evaluated for syncope in physicians' offices.[7] The estimated cost of evaluating patients with syncope is approximately $750 million annually.[7]

In the Framingham study,[8] 3.0 percent of 2,336 men and 3.5 percent of 2,873 women (combined mean age: 46 years) had an episode of syncope. Thirty percent of the men and 27 percent of the women with syncope had recurrent episodes.

The incidence of syncope has been found to increase with increasing age. In a study of 711 elderly patients 75 years of age or older living in a long-term care facility, the yearly incidence of syncope was 6 percent and the recurrence rate was 30 percent.[4,9]

Syncope is associated with high morbidity and mortality. The variety of injuries that may result from syncope or fainting range from small contusions and lacerations to major injuries such as cerebral concussions, subdural hematomas and hip fractures. In one study,[1] 37 percent of 204 patients evaluated for syncope had suffered physical injury. In addition, the underlying cause of syncope can have prognostic value. A cardiac cause of syncope has been associated with a one-year mortality rate as high as 30 percent (Table 1).[1,2,10,11]

Evaluation of Syncopal Patients

Table 2 lists the basic pathophysiologic causes of syncope. They can be grouped into six categories: (1) abnormalities of neuroautonomic regulation, (2) cardiac causes, including mechanical or electrophysiologic abnormalities, (3) underlying neurologic disorders such as seizure disorders, (4) abnormalities of metabolic or endocrine function, (5) psychiatric disturbances and (6) syncope of undetermined origin. The history and physical examination are particularly helpful in the evaluation of patients with syncope or near-syncope. In one study,[1] the cause of syncope was identified from the history and physical examination in 25 percent of the patients.

While a complete discussion of the approach to syncope is beyond the scope of this article, a brief algorithm for the evaluation of syncope is presented in Figure 1. Several recent articles provide an excellent review of this subject.[6,12,13]

Pathophysiology of Vasovagal Syncope

When a person moves to the upright position, 300 to 800 mL of blood is shifted from the thorax to the lower extremities and is lost from the central circulation.[14] Subsequently, the decreased central venous return reduces left ventricular filling, with an immediate drop in cardiac output and in arterial blood pressure. The carotid sinus and aortic arch baroreceptors reduce their inhibitory drive to the vasomotor center of the medulla and permit an increased sympathetic tone, with a rise in epinephrine and vasopressin levels, an increased heart rate, increased cardiac contractility and an increase in arteriolar resistance][15-17] and venous tone.[18] As a result, adequate blood pressure and cerebral perfusion are maintained (Figure 2).

In some individuals, the sudden onset of syncope results from an abnormal vasovagal reflex. The abnormal vasovagal response occurs because the compensatory mechanisms that occur in normal individuals on assuming an upright position are disrupted by a sudden drop in venous return to the heart. This reduction in venous return results in an increase in inotropy and, as the vigor of cardiac contractility increases, the left ventricular chamber size decreases while the wall stress increases. The mechanoreceptors, or nonmyelinated C-fibers, of the left ventricle paradoxically fire en masse resulting in an override of the carotid sinus and aortic arch baroreceptors.[15,17] This sudden surge in vagal afferent input to the brainstem somehow mimics the effects of hypertension, which in turn results in a paradoxic decrease in sympathetic tone and an overwhelming increase in vagal efferent tone. The clinical picture is that of hypotension secondary to vasodilatation from sympathetic withdrawal and an overriding vagal tone with bradycardia from direct vagal stimulation[17] (Figure 3).

During the orthostatic stress produced by the tilt test, an abnormal vasovagal response may occur and result in syncope or near-syncope (Figure 4). Vasovagal episodes as long as 72 seconds have been reported[19] (Figure 5).

Head-Upright Tilt Test

The head-upright tilt test has been used for a number of years in the laboratory to evaluate the human physiologic response to gravity.[20,21] Only recently has the tilt test become a clinical tool for the evaluation of patients with syncope of undetermined cause.[22] The tilt test serves as a means of determining which patients are susceptible to vasovagal (neurally mediated) syncope.[23-25]

The physiologic response to the upright tilt was described several decades ago[26] (Table 3). More recently, tilt testing has been used concurrently with cardiac electrophysiologic studies to evaluate the effect of cardiac arrhythmias on hemodynamic stability.[27]

Although vasovagal syncope is classically associated with a distinct prodrome of nausea, diaphoresis, dizziness and other warning signals, it is not always preceded by these symptoms. Vasovagal syncope may occur suddenly without warning. In one study,[22] 53 percent of patients sustaining syncope-related injury were shown by tilt testing to have vasovagal syncope.

Vasovagal syncope should not be confused with orthostatic hypotension,[12] Which is manifested during tilt testing by a sudden drop in blood pressure as soon as the patient is tilted. Vasovagal syncope occurs in patients who initially have a normal response (a rise in blood pressure and heart rate) on tilt testing. Patients with vasovagal syncope exhibit an inability to maintain homeostatic blood pressure and cerebral perfusion due to abnormalities of autonomic regulation.

Method of Tilt-Table Testing

A standard protocol for the head-upright tilt test has not yet been defined. Methods differ in regard to the angle of tilt (60 degrees or greater is generally used), the duration of time for the tilt test and the use of adjuvant drugs such as isoproterenol (Isuprel) to provoke the vasovagal response.[28-30] The head-upright tilt test described in this article, using an 80-degree tilt angle for 30 minutes and adjuvant isoproterenol if needed, is used by the Medical College of Ohio at Toledo and is similar to the protocol used by others.[30]

Usually, children[31] and adults are referred for evaluation of unexplained syncope after a thorough evaluation, which would include a history and physical examination, magnetic resonance imaging (MRI) or computed tomographic (CT) scanning of the head (when indicated), electroencephalography, cerebral blood flow evaluations, echocardiography, cardiac catheterization and cardiac electrophysiology studies.

Head-upright tilt-table testing is performed following six hours of fasting. When possible, it is performed in the morning to obviate the effect of cyclic variation in parasympathetic tone.[32] The patient is placed on a tilt table. An intravenous line is inserted, and continuous electrocardiographic monitoring is performed. In selected patients, transcranial Doppler cerebral blood flow[33] is continuously monitored, and in some patients continuous electroencephalographic monitoring is used.[34] The patient is secured to the tilt table with snug restraints to prevent the patient from falling if syncope occurs. Baseline hemodynamic parameters are measured, and the patient is tilted to an 80-degree head-upright position within 10 seconds (Figures 6 and 7).

Blood pressure is taken every three minutes, the heart rate is monitored, and symptoms and sign of the discomfort of syncope or near-syncope are constantly elicited. The baseline tilt lasts for 30 minutes or until syncope or near-syncope occurs. Vasovagal symptoms (nausea, lightheadedness, blurred vision and loss of sense of well-being) and signs (yawning, sweating, pallor, hypotension and bradycardia) rapidly resolve when the patient is returned to the supine position. If syncope does not occur after 30 minutes, the patient is returned to the supine position, and the tilt test is repeated using a continuous infusion of intravenous isoproterenol, 1 to 6 [Mu] g per minute, to increase the resting baseline heart rate by 20 percent.


Isoproterenol is added to the tilt-table testing regimen for two reasons.[28,30,35] An adrenergic agonist, isoproterenol can increase susceptibility to vasovagal syncope, since this reaction is triggered by a strong sympathetic stimulus. Early studies indicated that isoproterenol can also increase the sensitivity of the test by as much as 60 percent, without an appreciable change in specificity (Table 4).[30] Contrary evidence was recently reported in another study in which the specificity of tilt testing using isoproterenol in young adults was only 33 percent.[36] This study advised against adjuvant use of isoproterenol. To clarify this concern, further investigation is needed in this evolving area.

Convulsive Syncope vs. Epilepsy

Recognizing nonepileptic conditions that produce seizures is important. A misdiagnosis of epilepsy delays identification of the correct etiology and hinders therapy. Early in our experience, some patients displayed tonic-clonic seizure-like activity (convulsive syncope) during tilt test-induced syncope. It was postulated that some patients with the clinical presentation of epilepsy may actually have convulsive syncope.

In one study,[32] 15 patients with idiopathic, recurrent, generalized seizures refractory to therapy underwent head-upright tilt testing while in a drug-free state. Syncope associated with tonic-clonic seizure-like activity occurred in six patients (40 percent) during the initial tilt and in four patients (27 percent) during isoproterenol infusion. Five of the patients with positive results initially on tilt testing underwent a second drug-free tilt test with continuous electroencephalographic monitoring. In each of these patients, the electroencephalogram demonstrated a diffuse slowing indicative of cerebral hypoxia rather than the hypersynchronous spike wave activity usually seen in epilepsy (Figure 8).

These results suggest that tilt-table testing may be useful in differentiating convulsive syncope from epilepsy in patients with recurrent idiopathic seizures. Other investigators[37] reported similar findings with tilt testing among 16 patients who were found to have convulsive syncope during ocular compression testing.

Indications for Tilt Testing

The indications for tilt testing are currently evolving. Patients with unexplained syncope are diagnostically challenging. The integration of invasive and noninvasive studies before tilt testing must be considered. The decision to use tilt testing is based on the clinical situation. Certainly, the diagnosis of vasovagal-mediated syncope is attractive, since the prognosis is good and effective therapy exists. However, physicians should be careful not to overlook other serious coexisting problems, such as cardiac arrhythmias and seizure disorders.

Therapy for Vasovagal Syncope

Several principles guide therapy. [Beta.sub.1] adrenergic (cardioselective) blocking agents can prevent reflex hypotension and bradycardia, partly by their negative inotropic action.[29,34] Volume expansion with fludrocortisone acetate (Florinef Acetate), a salt-retaining mineralocorticoid, has also been employed.[35,38] Vagolytic agents (such as scopolamine and atropine) are believed to diminish the efferent hypervagotonia associated with this reflex and hence lessen the degree of induced bradycardia.[39]

Disopyramide (Napamide, Norpace) exhibits both negative inotropic actions and potent anticholinergic effects and has recently been found to reduce episodes of vasovagal syncope.[34,36] Disopyramide possesses a peripheral vasoconstrictive effect that may diminish symptoms in patients who develop hypotension, as opposed to a prominent bradycardia, during vasovagal syncope.[38]

Oral theophylline has proved effective in preventing recurrent episodes of syncope. Theophylline is thought to block the peripheral vasodilatory effects of adenosine.[40]

Cardiac pacemakers have been advocated in patients with severe bradycardia and prolonged periods of asystole[19,24] (Table 5).


Initial reports seem to support good results with tilt test-directed therapy for vasovagal syncope. In one study[35] of Medical therapy, prophylactic treatment prevented recurrent syncope over a 16-month period. In a 24-month study,[22]pacemakers resulted in abolition of symptoms in 21 of 40 patients.

Illustrative Case

A 27-year-old man presented to our clinic with a four-year history of epilepsy. His seizures were marked by sudden loss of consciousness without warning, marked cyanosis and tonic-clonic movements of the extremities. Serial use of phenytoin, valproic acid and carbamazepine were not effective in preventing seizures. Because of continued epileptic episodes, he underwent a tilt test with continuous electroencephalographic monitoring. Eight minutes into the study, he developed asystole, loss of consciousness and suffered a grand mal seizure.

Anticonvulsants were subsequently discontinued. The patient was placed on a beta blocker, but developed severe fatigue. His medicine was changed to fludrocortisone, which was partially effective. He now has a longer prodrome, which allows him to sit or lie down and abort most spells.

The authors thank Sherri Sweet, Pam Brewster, Daniela Samoil, M.D., and Mary D. Wolfe for help in the preparation of this manuscript.


[1.] Kapoor WN, Karpf M, Wieand S, Peterson JR, Levey GS. A prospective evaluation and follow-up of patients with syncope. N Engl J Med 1983;309:197-204. [2.] Silverstein MD, Singer DE, Mulley AG, Thibault GE, Barnett GO. Patients with syncope admitted to medical intensive care units. JAMA 1982;248:1185-9. [3.] Kapoor WN, Karpf M, Maher Y, Miller RA, Levey GS. Syncope of unknown origin. The need for a more cost-effective approach to its diagnostic evaluation. JAMA 982;247:2687-91. [4.] Whiteside-Yim C. Syncope in the elderly: a clinical approach. Geriatrics 1987;42(4):37-41. [5.] Hess DS, Morady F, Scheinman MM. Electrophysiologic testing in the evaluation of patients with syncope of undetermined origin. Am J Cardiol 1982;50:1309-15. [6.] Manolis AS, Linzer M, Salem D, Estes NA 3d. Syncope: current diagnostic evaluation and management. Ann Intern Med 1990;112: 850-63. [7.] Linzer M. Syncope: 1991 [Editorial]. Am J Med 1991;90:1-5. [8.] Savage DD, Corwin L, McGee DL, Kannel WB, Wolf PA. Epidemiologic features of isolated syncope: the Framingham Study. Stroke 1985;16:626-9. [9.] Lipsitz LA, Wei JY, Rowe JW. Syncope in an elderly, institutionalised population: prevalence, incidence, and associated risk. Q J Med 1985;55:45-54. [10.] Hurst JW, Schlant RC, Rackley CE, Sansenblock EH, Wenger NK. Syncope: pathophysiology, recognition and treatment. In: Hurst JW et al., eds. The heart, arteries and veins. 7th ed. New York: McGraw-Hill, 1990:582. [11.] Eagle KA, Black HR, Cook EF, et al. Evaluation of prognostic classifications of patients with syncope. Am J Med 1985; 79:455-60. [12.] Susman J. Orthostatic hypotension. Am Fam Physician 1988;37(6):115-8. [13.] Kapoor WN. Diagnostic evaluation of syncope. Am J Med 1991;90:91-106. [14.] Ibrahim MM, Tarazi RC, Dustan HP. Orthostatic hypotension: mechanisms and management. Am Heart J 1975;90:513-20. [15.] Miyamoto Y, Higuchi J, Mikami T. Cardiorespiratory dynamics during vasovagal syncope induced by a head-up tilt. Jpn J Physiol 1982;32:885-9. [16.] Glick G, Yu PN. Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 1963;34:542-51. [17.] Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1983;1:90-102. [18.] Epstein SE, Stampfer M, Beiser GD. Role of the capacitance and resistance vessels in vasovagal syncope. Circulation 1968;37:524-33. [19.] Maloney JD, Jaeger FJ, Fouad-Tarazi FM, Morris HH. Malignant vasovagal syncope: prolonged asystole provoked by head-up tilt. Case report and review of diagnosis, pathophysiology, and therapy. Cleve Clin J Med 1988; 55:542-8. [20.] Abelman WH, Farceduddin K. Circulatory response to upright tilt in patients with heart disease. Aerospace Med 1967;38:60. [21.] Shvartz E, Meyerstein N. Tilt tolerance of young men and young women. Aerospace Med 1970;41:253-5. [22.] Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1986;1(8494): 1352-5. [23.] Strasberg B, Rechavia E, Sagie A, et al. The head-up tilt table test in patients with syncope of unknown origin. Am Heart J 1989;118(5 Pt 1):923-7. [24.] Fitzpatrick A, Sutton R. Tilting towards a diagnosis in recurrent unexplained syncope. Lancet 1989;1(8639):658-60. [25.] Raviele A, Gasparini G, Di Pede F, Delise P, Bonso A, Piccolo E. Usefulness of head-up tilt test in evaluating patients with syncope of unknown origin and negative electrophysiologic study. Am J Cardiol 1990;65:1322-7. [26.] Lagerlof H, Eliasch H, Werko L, Berglund E. Orthostatic changes of the pulmonary and peripheral circulation in man. A preliminary report. Scand J Clin Lab Invest 1951;3:85-91. [27.] Hammill SC, Holmes DR Jr, Wood DL, et al. Electrophysiologic testing in the upright position: improved evaluation of patients with rhythm disturbances using a tilt table. J Am Coll Cardiol 1984;4:65-71. [28.] Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol 1989; 63:58-65. [29.] Abi-Samra F, Maloney JD, Fouad-Tarazi FM, Castle LW. The usefulness of head-up tilt testing and hemodynamic investigations in the workup of syncope of unknown origin. PACE Pacing Clin Electrophysiol 1988;11:1202-14. [30.] Almquist A, Goldenberg IF, Milstein S, et al. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Eng] J Med 1989;320:346-51. [31.] Thilenius OG, Quinones JA, Husayni TS, Novak J. Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics 1991; 87:334-8. [32.] Fouad FM, Tarazi RC, Ferrario CM, Fighaly S, Alicandri C. Assessment of parasympathetic control of heart rate by a noninvasive method. Am J Physiol 1984;246(6 Pt 2):H838-42. [33.] Grubb BP, Gerard G, Roush K, et al. Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope. A paradoxic and unexpected response. Circulation 1991;84: 1157-64. [34.] Grubb BP, Gerard G, Roush K, et al. Differentiation of convulsive syncope and epilepsy with head-up tilt testing. Ann Intern Med 1991;115:871-6. [35.] Grubb BP, Temesy-Armos P, Hahn H, Elliott L. Utility of upright tilt-table testing in the evaluation and management of syncope of unknown origin. Am J Med 1991;90:6-10. [36.] Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol: a nonspecific test. Ann Intern Med 1992;116: 358-63. [37.] Jaeger F, Schneider L, Maloney JD, Cruse RP, Fouad-Tarazi FM. Vasovagal syncope: diagnostic role of head-up tilt test in patients with a positive ocular compression test. PACE Pacing Clin Electrophysiol 1990; 13(11 Pt 1): 1416-23. [38.] Milstein S, Buetikofer J, Dunnigan A, Benditt DG, Gornick C, Reyes WJ. Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia. Am J Cardiol 1990;65:1339-44. [39.] McLaran CJ, Gersh BJ, Osborn MJ, et al. Increased vagal tone as an isolated finding in patients undergoing electrophysiological testing for recurrent syncope: response to long term anticholinergic agents. Br Heart J 1986; 55:53-7. [40.] Nelson SD, Stanley M, Love CJ, Coyne KS, Schaal SF. The autonomic and hemodynamic effects of oral theophylline in patients with vasodepressor syncope. Arch Intern Med 1991;151:2425-9.

The Authors

DOUGLAS A. WOLFE, M.D. is a cardiology fellow at the Medical College of Ohio, Toledo. a graduate of the Medical University of South Carolina, Charleston, he completed a family practice residency at Spartanburg (S.C.) Regional Medical Center, and an internal medicine residency at the Medical University of South Carolina. Dr. Wolfe is currently doing clinical research in autonomic dysfunction and its relationship to syncope. BLAIR P. GRUBB, M.D. is assistant professor of medicine at the Medical College of Ohio, where he is also co-director of the electrophysiology laboratory. He completed an internal medicine residency at the Greater Baltimore Medical Center and cardiology and electrophysiology fellowships at Pennsylvania State University, Hershey. Dr. Grubb's research interests include the mechanism and management of syncope. SANFORD R. KIMMEL, M.D. is associate professor of clinical family medicine at the Medical College of Ohio. A graduate of the Ohio State University School of Medicine, Columbus, he completed a family practice residency at Saint Elizabeth Medical Center in Dayton, Ohio, and two years of pediatrics training at Columbus (Ohio) Children's Hospital.

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