782 Current Perspectives Diagnostic Criteria for the Long QT Syndrome An Update Peter J. Schwartz, MD; Arthur J. Moss, MD; G. Michael Vincent, MD; Richard S. Crampton, MD T he idiopathic long QT syndrome (LQTS) is a congenital disease with frequent familial trans- mission, characterized primarily by prolonga- tion of the QT interval and by the occurrence of life-threatening tachyarrhythmias, particularly in asso- ciation with emotional or physical stress.1-5 Among untreated symptomatic patients, lethality is high, with 20% mortality in the first year after the initial syncope and approximately 50% within 10 years3; however, the risk of death varies among different families. This poor prognosis has been significantly improved by the use of pharmacological or surgical antiadrenergic therapy or both, which has reduced long-term mortality to <5%.3,4,6 The availability of effective therapy for this often lethal disease emphasizes the importance of early and accurate diagnosis. Unfortunately, there is fre- quently a delay in the diagnosis of LQTS, and patients with syncope are often misdiagnosed, most commonly as affected by a seizure disorder. In its most characteristic presentation, with obvious QT prolongation and stress-induced syncope, the diag- nosis of LQTS is quite straightforward for physicians aware of the disease. In cases of borderline QT prolon- gation and/or absence of symptoms, however, a correct diagnosis may be more difficult. It was for this reason that a first set of diagnostic criteria (Table 1) was proposed in 1985.3 The major merit of that proposal was that it provided a logical and quantitative approach to the clinical diagnosis of LQTS by giving a different weight to major and minor criteria. Its major limitation was that it used the traditional, but untested for diag- nostic purposes, cutoff value of QT, >440 msec '2. This also resulted in a rather black-and-white situation in which patients were judged to have an entirely normal or abnormal duration of ventricular repolarization on the basis of a difference of a few milliseconds in a measurement fraught with difficulties, such as interob- server variability.7 Received November 2, 1992; revision accepted March 29, 1993. From the Istituto di Clinica Medica II, University of Milan, and Department of Medicine, University of Pavia, Italy (PJ.S.); the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (A.J.M.); the Department of Medicine, LDS Hospital, University of Utah Health Sciences Center, Salt Lake City, Utah (G.M.V.); and the Department of Medicine, University of Virginia School of Medicine, Charlottes- ville, Va (R.S.C.). Correspondence to Peter J. Schwartz, MD, Istituto di Clinica Medica II, Universita di Milano, Via F. Sforza, 35, 20122 Milano, Italy. Three events have contributed to a reassessment of those diagnostic criteria. The first has been the quanti- fication of the traditionally known but previously poorly documented sex-related differences in the duration of ventricular repolarization. Merri et a18 analyzed a large series of normal individuals and found that the aver- age QT, values were significantly longer among women than men (421+18 versus 409±14 msec'2, P<.0001). These data suggest that different QT, criteria are nec- essary for men versus women and that approximately <2.5% of normal men and women have QT, values >440 and >460 msec 12, respectively. The second event has been the progressive realization that the spectrum of clinical abnormalities observed in LQTS is larger than previously realized and that it includes several features that might contribute to a more accurate diagnosis. These abnormalities have been documented, almost always in case-control stud- ies, to occur frequently in LQTS patients and quite rarely among healthy control subjects. They include the following: (1) a larger than normal area of negative potentials in the anterior chest leads and a complex multipolar distribution as assessed by body surface mapping.9-11 These findings suggest the presence of delayed repolarization of the anterior ventricular wall, of regional electrical disparities in the recovery process, and of a high degree of dispersion of ventricular recov- ery times. (2) Several other quantifiable components of ventricular repolarization in addition to the QT interval are prolonged among LQTS patients.12 (3) Two peculiar mechanical abnormalities have been demonstrated by echocardiography, namely, a more rapid early contrac- tion and a much longer time spent at a very low thickening rate just before the fast relaxation.13 (4) Peculiar changes in the T wave and an abnormal relation of QT interval to cycle length changes during and early after exercise.14-16 (5) Bifid or notched T waves are frequently present in several ECG leads.17 Since some of these recently described abnormalities have not yet been confirmed by other investigators or, as in the case of body surface maps, are not readily observed, they have not been entered into the new diagnostic criteria. However, they may become valuable diagnostic tools and may be included in subsequent versions of diagnostic criteria. At this time, these addi- tional clinical features may already be of practical value when dealing with borderline patients, those identified by the new diagnostic criteria as having an "intermedi- ate probability of LQTS." Downloaded from http://ahajournals.org by on March 3, 2023
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Diagnostic criteria for the long QT syndrome. An update.Diagnostic Criteria for the Long QT Syndrome An Update
Peter J. Schwartz, MD; Arthur J. Moss, MD; G. Michael Vincent, MD; Richard S. Crampton, MD
T he idiopathic long QT syndrome (LQTS) is a congenital disease with frequent familial trans- mission, characterized primarily by prolonga-
tion of the QT interval and by the occurrence of life-threatening tachyarrhythmias, particularly in asso- ciation with emotional or physical stress.1-5 Among untreated symptomatic patients, lethality is high, with 20% mortality in the first year after the initial syncope and approximately 50% within 10 years3; however, the risk of death varies among different families. This poor prognosis has been significantly improved by the use of pharmacological or surgical antiadrenergic therapy or both, which has reduced long-term mortality to <5%.3,4,6 The availability of effective therapy for this often lethal disease emphasizes the importance of early and accurate diagnosis. Unfortunately, there is fre- quently a delay in the diagnosis of LQTS, and patients with syncope are often misdiagnosed, most commonly as affected by a seizure disorder.
In its most characteristic presentation, with obvious QT prolongation and stress-induced syncope, the diag- nosis of LQTS is quite straightforward for physicians aware of the disease. In cases of borderline QT prolon- gation and/or absence of symptoms, however, a correct diagnosis may be more difficult. It was for this reason that a first set of diagnostic criteria (Table 1) was proposed in 1985.3 The major merit of that proposal was that it provided a logical and quantitative approach to the clinical diagnosis of LQTS by giving a different weight to major and minor criteria. Its major limitation was that it used the traditional, but untested for diag- nostic purposes, cutoff value of QT, >440 msec '2. This also resulted in a rather black-and-white situation in which patients were judged to have an entirely normal or abnormal duration of ventricular repolarization on the basis of a difference of a few milliseconds in a measurement fraught with difficulties, such as interob- server variability.7
Received November 2, 1992; revision accepted March 29, 1993. From the Istituto di Clinica Medica II, University of Milan, and
Department of Medicine, University of Pavia, Italy (PJ.S.); the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (A.J.M.); the Department of Medicine, LDS Hospital, University of Utah Health Sciences Center, Salt Lake City, Utah (G.M.V.); and the Department of Medicine, University of Virginia School of Medicine, Charlottes- ville, Va (R.S.C.).
Correspondence to Peter J. Schwartz, MD, Istituto di Clinica Medica II, Universita di Milano, Via F. Sforza, 35, 20122 Milano, Italy.
Three events have contributed to a reassessment of those diagnostic criteria. The first has been the quanti- fication of the traditionally known but previously poorly documented sex-related differences in the duration of ventricular repolarization. Merri et a18 analyzed a large series of normal individuals and found that the aver- age QT, values were significantly longer among women than men (421+18 versus 409±14 msec'2, P<.0001). These data suggest that different QT, criteria are nec- essary for men versus women and that approximately <2.5% of normal men and women have QT, values >440 and >460 msec 12, respectively. The second event has been the progressive realization
that the spectrum of clinical abnormalities observed in LQTS is larger than previously realized and that it includes several features that might contribute to a more accurate diagnosis. These abnormalities have been documented, almost always in case-control stud- ies, to occur frequently in LQTS patients and quite rarely among healthy control subjects. They include the following: (1) a larger than normal area of negative potentials in the anterior chest leads and a complex multipolar distribution as assessed by body surface mapping.9-11 These findings suggest the presence of delayed repolarization of the anterior ventricular wall, of regional electrical disparities in the recovery process, and of a high degree of dispersion of ventricular recov- ery times. (2) Several other quantifiable components of ventricular repolarization in addition to the QT interval are prolonged among LQTS patients.12 (3) Two peculiar mechanical abnormalities have been demonstrated by echocardiography, namely, a more rapid early contrac- tion and a much longer time spent at a very low thickening rate just before the fast relaxation.13 (4) Peculiar changes in the T wave and an abnormal relation of QT interval to cycle length changes during and early after exercise.14-16 (5) Bifid or notched T waves are frequently present in several ECG leads.17 Since some of these recently described abnormalities have not yet been confirmed by other investigators or, as in the case of body surface maps, are not readily observed, they have not been entered into the new diagnostic criteria. However, they may become valuable diagnostic tools and may be included in subsequent versions of diagnostic criteria. At this time, these addi- tional clinical features may already be of practical value when dealing with borderline patients, those identified by the new diagnostic criteria as having an "intermedi- ate probability of LQTS."
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TABLE 1. 1985 LQTS Diagnostic Criteria
Major Minor
Prolonged QT interval (QTC >440 msec) Congenital deafness Stress-induced syncope Episodes of T-wave alternans Family members with LQTS Low heart rate (in children)
Abnormal ventricular repolarization
LQTS, long QT syndrome. The diagnosis of LQTS is made in the presence of either two major criteria or of one major and two
minor criteria.
The third event has been the contribution of molec- ular biology to the genetic understanding of LQTS.18 Keating et a119 found linkage in three LQTS families with a DNA marker at the Harvey ras-1 locus, located on the short arm of chromosome 11. This linkage has been confirmed in some additional families20,21 but not in others.22 This supports the concept of genetic heter- ogeneity in LQTS, a notion that reflects the differences in clinical manifestations and particularly in the degree of malignancy known to be present in LQTS families. After Harvey ras-1 linkage had been identified, Vincent et a122 described the range of QT. of 83 LQTS gene carriers and 199 noncarriers. Several findings emerged. First, a large overlap of QT, values existed between carriers and noncarriers; the overlap range was 410 to 465 msec112 and included about 60% of all 242 study subjects. Second, approximately 5% of LQTS gene carriers (all males) had QT. values <440 msec 12, con- firming previous suspicions of "normal QTc" LQTS patients.23 Third, the sex difference in QT. values was confirmed for LQTS patients, since a QTc of >480 msec1/2 in females and of .470 msec112 in males was 100% predictive of positive linkage. These findings emphasized the limitations of QT, measurement for LQTS diagnosis; indicated that any single QT, cutoff point might lead to misclassifications and, therefore, that a variable weighting of QT. was necessary; and further supported the need for non-ECG criteria for LQTS diagnosis.
It was on the basis of these developments and of the attendant implications that we felt it necessary to upgrade the criteria for diagnosing LQTS. The new diagnostic criteria are listed in Table 2, with relative points assigned to various ECG, clinical, and familial findings. The score ranges from a minimum value of 0 to a maximum value of 9 points. On the basis of our experience, we have arbitrarily divided the point score into three probability categories: (1) c1 point, low probability of LQTS; (2) 2 or 3 points, intermediate probability of LQTS; and (3) >4 points, high probabil- ity of LQTS. Since QT, overcorrects at fast heart rates, additional diagnostic caution is necessary when scaling with a tachycardiac patient.
Note, QT. >480 msec1/2 is assigned the highest value (3 points), but QT. prolongation (QTC >450 msec112) per se is not an absolute prerequisite for the diagnosis of LQTS. Note also that torsade de pointes and syncope with stress are each assigned a value of 2 points, but they are mutually exclusive. Torsade de pointes receives no points if the patient is taking drugs known to favor QT prolongation. We felt it important to include some aspect of family history in the diagnostic criteria, but we assigned low point values for the presence of family
members with overt manifestations of the disease to avoid a potentially excessive hereditary bias. The diag- nostic weight of "lower-than-normal" heart rate also has now been reduced and is restricted to children24; we suggest using the lower second percentile from the large study by Davignon et al.25 T-wave alternans is defined as the regular alternation, in amplitude or in polarity, of two different configurations of T wave while the RR interval remains unmodified.26 This type of T-wave alternans is rather gross and does not need, for its detection, sophisticated computerized analyses.27,28 When a patient receives a score of 2 or 3 points on the
basis of the QT interval measurement, we suggest obtaining serial ECG records, because the QT, value in LQTS patients may vary from time to time. In this group, with an intermediate probability of LQTS, the presence of the more recently described abnormalities listed earlier may be of help to the physician in his or her diagnostic and therapeutic decisions. These patients
TABLE 2. 1993 LQTS Diagnostic Criteria
Points
2480 msec"l2 460-470 msec/12 450 msec112 (in males)
B. Torsade de pointest C. T-Wave alternans D. Notched T wave in three leads E. Low heart rate for age§
Clinical history A. Syncope*
With stress Without stress
2 1
B. Congenital deafness 0.5 Family history
A. Family members with definite LQTS# 1 B. Unexplained sudden cardiac death below age 30
among immediate family members 0.5
LQTS, long QT syndrome. *In the absence of medications or disorders known to affect
these electrocardiographic features. tQTc calculated by Bazett's formula, where QT,=QT/R. *Mutually exclusive. §Resting heart rate below the second percentile for age.25 liThe same family member cannot be counted in A and B. #Definite LOTS is defined by an LQTS score >4. Scoring: <1 point, low probability of LQTS; 2 to 3 points,
intermediate probability of LOTS; >4 points, high probability of LOTS.
783
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784 Circulation Vol 88, No 2 August 1993
certainly deserve to be followed carefully over time for the possible appearance of a more definitive diagnostic clue. Any set of diagnostic criteria involving a quantitative
score has an unavoidable arbitrary component, and we believe that, as time progresses, further updates will be possible. On the other hand, this scoring system incor- porates and reflects >20 years of direct personal expe- rience with LOTS shared by the authors. We also believe that, based on present knowledge, these diag- nostic criteria represent a valid tool to facilitate the correct diagnosis of LOTS and to increase the number of affected patients who are recognized as such and who accordingly can benefit from promptly receiving the proper therapy.
Acknowledgment This study was supported in part by National Institutes of
Health grant HL-33843.
References 1. Vincent GM, Abildskov JA, Burgess MJ. Q-T interval syndromes.
Prog Cardiovasc Dis. 1974;16:523-530. 2. Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am
Heart J. 1975;89:378-390. 3. Schwartz PJ. Idiopathic long QT syndrome: progress and ques-
tions. Am Heart J. 1985;2:399-411. 4. Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The
long QT syndrome: a prospective international study. Circulation. 1985;71:17-21.
5. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A, Rob- inson JL, Benhorin J, Choi S. The long QT syndrome: prospective longitudinal study of 328 families. Circulation. 1991;84:1136-1144.
6. Schwartz PJ, Locati EH, Moss AJ, Crampton RS, Trazzi R, Ruberti U. Left cardiac sympathetic denervation in the therapy of the congenital long QT syndrome: a worldwide report. Circulation. 1991;84:503-511.
7. Butrous GS, Schwartz PJ, eds. Clinical Aspects of Ventricular Repo- larization. London: Farrand Press; 1989:498.
8. Merri M, Benhorin J, Alberti M, Locati E, Moss AJ. Electrocar- diographic quantitation of ventricular repolarization. Circulation. 1989;80:1301-1308.
9. De Ambroggi L, Bertoni T, Locati E, Stramba-Badiale M, Schwartz PJ. Mapping of body surface potentials in patients with idiopathic long QT syndrome. Circulation. 1986;74:1334-1345.
10. De Ambroggi L, Monza E, Bertoni T, Negroni MS, Schwartz PJ. Analysis of ventricular repolarization in patients with the long QT syndrome: detection of indices of electrical disparities. Am J Car- diol. 1991;68:614-620.
11. Abildskov JA, Vincent GM, Evans AK, Burgess MJ. Distribution of body surface ECG potentials in familial QT interval prolonga- tion. Am J Cardiol. 1981;47:480. Abstract.
12. Benhorin J, Merri M, Alberti M, Locati E, Moss AJ, Hall WJ, Cui L. The long QT syndrome: new electrocardiographic characteris- tics. Circulation. 1990;82:521-527.
13. Nador F, Beria G, De Ferrari GM, Stramba-Badiale M, Locati EH, Lotto A, Schwartz PJ. Unsuspected echocardiographic abnor- mality in the long Q-T syndrome: diagnostic, prognostic, and pathogenetic implications. Circulation. 1991;84:1530-1542.
14. Locati EH, Pancaldi A, Pala M, Schwartz PJ. Exercise-induced electrocardiographic changes in patients with the long QT syn- drome. Circulation. 1988;78(suppl II):II-42. Abstract.
15. Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol. 1991;68:498-503.
16. Sala S, Malfatto G, Locati EH, De Ferrari GM, Schwartz PJ. Diagnostic value of exercise-induced T wave abnormalities in the idiopathic long QT syndrome. Circulation. 1992;86(suppl I):I-392. Abstract.
17. Malfatto G, Beria G, Sala S, Bonazzi 0, Schwartz PJ. Prognostic significance of T wave abnormalities in the idiopathic long QT syndrome. Circulation. 1990;82(suppl III):III-54. Abstract.
18. Keating M. Linkage analysis and long QT syndrome: using genetics to study cardiovascular disease. Circulation. 1992;85:1973-1986.
19. Keating M, Atkinson D, Dunn G, Timothy K, Vincent GM, Lep- pert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704-706.
20. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Lep- part M. Linkage of the long QT syndrome to the Harvey ras-1 locus on chromosome 11. Am J Hum Genet. 1991;49:1335-1339.
21. Towbin JA, Pagotto L, Siu B, Robinson J, Moss AJ, McCabe ERB, Hejtmancik JF. Romano-Ward long QT syndrome (RWLQTS): evidence of genetic heterogeneity. Pediatr Res. 1992;31:23A. Abstract.
22. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the long QT syndrome gene. N Engi J Med. 1992;327:846-852.
23. Schwartz PJ. The longQT syndrome. In: Kulbertus HE, Wellens HJJ, eds. Sudden Death. The Hague: Martinus Nijhoff; 1980:358-378.
24. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J. 1986;112:61-64.
25. Davignon A, Rautaharju B, Boisselle E, Soumis F, Megelas M, Choquette A. Normal ECG standards for infants and children. Pediatr CardioL 1980;1:123-130.
26. Schwartz PJ, Malliani A. Electrical alternation of the T wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long QT syndrome. Am Heart J. 1975;89:45-50.
27. Smith JM, Clancy EA, Valeri CR, Ruskin JN, Cohen RJ. Electrical alternans and cardiac electrical instability. Circulation. 1988;77: 110-121.
28. Nearing BD, Huang AH, Verrier RL. Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave. Science. 1991;252:437-440.
KEY WoRDs llong QT syndrome * Current Perspectives
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arch 3, 2023
Peter J. Schwartz, MD; Arthur J. Moss, MD; G. Michael Vincent, MD; Richard S. Crampton, MD
T he idiopathic long QT syndrome (LQTS) is a congenital disease with frequent familial trans- mission, characterized primarily by prolonga-
tion of the QT interval and by the occurrence of life-threatening tachyarrhythmias, particularly in asso- ciation with emotional or physical stress.1-5 Among untreated symptomatic patients, lethality is high, with 20% mortality in the first year after the initial syncope and approximately 50% within 10 years3; however, the risk of death varies among different families. This poor prognosis has been significantly improved by the use of pharmacological or surgical antiadrenergic therapy or both, which has reduced long-term mortality to <5%.3,4,6 The availability of effective therapy for this often lethal disease emphasizes the importance of early and accurate diagnosis. Unfortunately, there is fre- quently a delay in the diagnosis of LQTS, and patients with syncope are often misdiagnosed, most commonly as affected by a seizure disorder.
In its most characteristic presentation, with obvious QT prolongation and stress-induced syncope, the diag- nosis of LQTS is quite straightforward for physicians aware of the disease. In cases of borderline QT prolon- gation and/or absence of symptoms, however, a correct diagnosis may be more difficult. It was for this reason that a first set of diagnostic criteria (Table 1) was proposed in 1985.3 The major merit of that proposal was that it provided a logical and quantitative approach to the clinical diagnosis of LQTS by giving a different weight to major and minor criteria. Its major limitation was that it used the traditional, but untested for diag- nostic purposes, cutoff value of QT, >440 msec '2. This also resulted in a rather black-and-white situation in which patients were judged to have an entirely normal or abnormal duration of ventricular repolarization on the basis of a difference of a few milliseconds in a measurement fraught with difficulties, such as interob- server variability.7
Received November 2, 1992; revision accepted March 29, 1993. From the Istituto di Clinica Medica II, University of Milan, and
Department of Medicine, University of Pavia, Italy (PJ.S.); the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (A.J.M.); the Department of Medicine, LDS Hospital, University of Utah Health Sciences Center, Salt Lake City, Utah (G.M.V.); and the Department of Medicine, University of Virginia School of Medicine, Charlottes- ville, Va (R.S.C.).
Correspondence to Peter J. Schwartz, MD, Istituto di Clinica Medica II, Universita di Milano, Via F. Sforza, 35, 20122 Milano, Italy.
Three events have contributed to a reassessment of those diagnostic criteria. The first has been the quanti- fication of the traditionally known but previously poorly documented sex-related differences in the duration of ventricular repolarization. Merri et a18 analyzed a large series of normal individuals and found that the aver- age QT, values were significantly longer among women than men (421+18 versus 409±14 msec'2, P<.0001). These data suggest that different QT, criteria are nec- essary for men versus women and that approximately <2.5% of normal men and women have QT, values >440 and >460 msec 12, respectively. The second event has been the progressive realization
that the spectrum of clinical abnormalities observed in LQTS is larger than previously realized and that it includes several features that might contribute to a more accurate diagnosis. These abnormalities have been documented, almost always in case-control stud- ies, to occur frequently in LQTS patients and quite rarely among healthy control subjects. They include the following: (1) a larger than normal area of negative potentials in the anterior chest leads and a complex multipolar distribution as assessed by body surface mapping.9-11 These findings suggest the presence of delayed repolarization of the anterior ventricular wall, of regional electrical disparities in the recovery process, and of a high degree of dispersion of ventricular recov- ery times. (2) Several other quantifiable components of ventricular repolarization in addition to the QT interval are prolonged among LQTS patients.12 (3) Two peculiar mechanical abnormalities have been demonstrated by echocardiography, namely, a more rapid early contrac- tion and a much longer time spent at a very low thickening rate just before the fast relaxation.13 (4) Peculiar changes in the T wave and an abnormal relation of QT interval to cycle length changes during and early after exercise.14-16 (5) Bifid or notched T waves are frequently present in several ECG leads.17 Since some of these recently described abnormalities have not yet been confirmed by other investigators or, as in the case of body surface maps, are not readily observed, they have not been entered into the new diagnostic criteria. However, they may become valuable diagnostic tools and may be included in subsequent versions of diagnostic criteria. At this time, these addi- tional clinical features may already be of practical value when dealing with borderline patients, those identified by the new diagnostic criteria as having an "intermedi- ate probability of LQTS."
D ow
arch 3, 2023
TABLE 1. 1985 LQTS Diagnostic Criteria
Major Minor
Prolonged QT interval (QTC >440 msec) Congenital deafness Stress-induced syncope Episodes of T-wave alternans Family members with LQTS Low heart rate (in children)
Abnormal ventricular repolarization
LQTS, long QT syndrome. The diagnosis of LQTS is made in the presence of either two major criteria or of one major and two
minor criteria.
The third event has been the contribution of molec- ular biology to the genetic understanding of LQTS.18 Keating et a119 found linkage in three LQTS families with a DNA marker at the Harvey ras-1 locus, located on the short arm of chromosome 11. This linkage has been confirmed in some additional families20,21 but not in others.22 This supports the concept of genetic heter- ogeneity in LQTS, a notion that reflects the differences in clinical manifestations and particularly in the degree of malignancy known to be present in LQTS families. After Harvey ras-1 linkage had been identified, Vincent et a122 described the range of QT. of 83 LQTS gene carriers and 199 noncarriers. Several findings emerged. First, a large overlap of QT, values existed between carriers and noncarriers; the overlap range was 410 to 465 msec112 and included about 60% of all 242 study subjects. Second, approximately 5% of LQTS gene carriers (all males) had QT. values <440 msec 12, con- firming previous suspicions of "normal QTc" LQTS patients.23 Third, the sex difference in QT. values was confirmed for LQTS patients, since a QTc of >480 msec1/2 in females and of .470 msec112 in males was 100% predictive of positive linkage. These findings emphasized the limitations of QT, measurement for LQTS diagnosis; indicated that any single QT, cutoff point might lead to misclassifications and, therefore, that a variable weighting of QT. was necessary; and further supported the need for non-ECG criteria for LQTS diagnosis.
It was on the basis of these developments and of the attendant implications that we felt it necessary to upgrade the criteria for diagnosing LQTS. The new diagnostic criteria are listed in Table 2, with relative points assigned to various ECG, clinical, and familial findings. The score ranges from a minimum value of 0 to a maximum value of 9 points. On the basis of our experience, we have arbitrarily divided the point score into three probability categories: (1) c1 point, low probability of LQTS; (2) 2 or 3 points, intermediate probability of LQTS; and (3) >4 points, high probabil- ity of LQTS. Since QT, overcorrects at fast heart rates, additional diagnostic caution is necessary when scaling with a tachycardiac patient.
Note, QT. >480 msec1/2 is assigned the highest value (3 points), but QT. prolongation (QTC >450 msec112) per se is not an absolute prerequisite for the diagnosis of LQTS. Note also that torsade de pointes and syncope with stress are each assigned a value of 2 points, but they are mutually exclusive. Torsade de pointes receives no points if the patient is taking drugs known to favor QT prolongation. We felt it important to include some aspect of family history in the diagnostic criteria, but we assigned low point values for the presence of family
members with overt manifestations of the disease to avoid a potentially excessive hereditary bias. The diag- nostic weight of "lower-than-normal" heart rate also has now been reduced and is restricted to children24; we suggest using the lower second percentile from the large study by Davignon et al.25 T-wave alternans is defined as the regular alternation, in amplitude or in polarity, of two different configurations of T wave while the RR interval remains unmodified.26 This type of T-wave alternans is rather gross and does not need, for its detection, sophisticated computerized analyses.27,28 When a patient receives a score of 2 or 3 points on the
basis of the QT interval measurement, we suggest obtaining serial ECG records, because the QT, value in LQTS patients may vary from time to time. In this group, with an intermediate probability of LQTS, the presence of the more recently described abnormalities listed earlier may be of help to the physician in his or her diagnostic and therapeutic decisions. These patients
TABLE 2. 1993 LQTS Diagnostic Criteria
Points
2480 msec"l2 460-470 msec/12 450 msec112 (in males)
B. Torsade de pointest C. T-Wave alternans D. Notched T wave in three leads E. Low heart rate for age§
Clinical history A. Syncope*
With stress Without stress
2 1
B. Congenital deafness 0.5 Family history
A. Family members with definite LQTS# 1 B. Unexplained sudden cardiac death below age 30
among immediate family members 0.5
LQTS, long QT syndrome. *In the absence of medications or disorders known to affect
these electrocardiographic features. tQTc calculated by Bazett's formula, where QT,=QT/R. *Mutually exclusive. §Resting heart rate below the second percentile for age.25 liThe same family member cannot be counted in A and B. #Definite LOTS is defined by an LQTS score >4. Scoring: <1 point, low probability of LQTS; 2 to 3 points,
intermediate probability of LOTS; >4 points, high probability of LOTS.
783
arch 3, 2023
784 Circulation Vol 88, No 2 August 1993
certainly deserve to be followed carefully over time for the possible appearance of a more definitive diagnostic clue. Any set of diagnostic criteria involving a quantitative
score has an unavoidable arbitrary component, and we believe that, as time progresses, further updates will be possible. On the other hand, this scoring system incor- porates and reflects >20 years of direct personal expe- rience with LOTS shared by the authors. We also believe that, based on present knowledge, these diag- nostic criteria represent a valid tool to facilitate the correct diagnosis of LOTS and to increase the number of affected patients who are recognized as such and who accordingly can benefit from promptly receiving the proper therapy.
Acknowledgment This study was supported in part by National Institutes of
Health grant HL-33843.
References 1. Vincent GM, Abildskov JA, Burgess MJ. Q-T interval syndromes.
Prog Cardiovasc Dis. 1974;16:523-530. 2. Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am
Heart J. 1975;89:378-390. 3. Schwartz PJ. Idiopathic long QT syndrome: progress and ques-
tions. Am Heart J. 1985;2:399-411. 4. Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The
long QT syndrome: a prospective international study. Circulation. 1985;71:17-21.
5. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A, Rob- inson JL, Benhorin J, Choi S. The long QT syndrome: prospective longitudinal study of 328 families. Circulation. 1991;84:1136-1144.
6. Schwartz PJ, Locati EH, Moss AJ, Crampton RS, Trazzi R, Ruberti U. Left cardiac sympathetic denervation in the therapy of the congenital long QT syndrome: a worldwide report. Circulation. 1991;84:503-511.
7. Butrous GS, Schwartz PJ, eds. Clinical Aspects of Ventricular Repo- larization. London: Farrand Press; 1989:498.
8. Merri M, Benhorin J, Alberti M, Locati E, Moss AJ. Electrocar- diographic quantitation of ventricular repolarization. Circulation. 1989;80:1301-1308.
9. De Ambroggi L, Bertoni T, Locati E, Stramba-Badiale M, Schwartz PJ. Mapping of body surface potentials in patients with idiopathic long QT syndrome. Circulation. 1986;74:1334-1345.
10. De Ambroggi L, Monza E, Bertoni T, Negroni MS, Schwartz PJ. Analysis of ventricular repolarization in patients with the long QT syndrome: detection of indices of electrical disparities. Am J Car- diol. 1991;68:614-620.
11. Abildskov JA, Vincent GM, Evans AK, Burgess MJ. Distribution of body surface ECG potentials in familial QT interval prolonga- tion. Am J Cardiol. 1981;47:480. Abstract.
12. Benhorin J, Merri M, Alberti M, Locati E, Moss AJ, Hall WJ, Cui L. The long QT syndrome: new electrocardiographic characteris- tics. Circulation. 1990;82:521-527.
13. Nador F, Beria G, De Ferrari GM, Stramba-Badiale M, Locati EH, Lotto A, Schwartz PJ. Unsuspected echocardiographic abnor- mality in the long Q-T syndrome: diagnostic, prognostic, and pathogenetic implications. Circulation. 1991;84:1530-1542.
14. Locati EH, Pancaldi A, Pala M, Schwartz PJ. Exercise-induced electrocardiographic changes in patients with the long QT syn- drome. Circulation. 1988;78(suppl II):II-42. Abstract.
15. Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol. 1991;68:498-503.
16. Sala S, Malfatto G, Locati EH, De Ferrari GM, Schwartz PJ. Diagnostic value of exercise-induced T wave abnormalities in the idiopathic long QT syndrome. Circulation. 1992;86(suppl I):I-392. Abstract.
17. Malfatto G, Beria G, Sala S, Bonazzi 0, Schwartz PJ. Prognostic significance of T wave abnormalities in the idiopathic long QT syndrome. Circulation. 1990;82(suppl III):III-54. Abstract.
18. Keating M. Linkage analysis and long QT syndrome: using genetics to study cardiovascular disease. Circulation. 1992;85:1973-1986.
19. Keating M, Atkinson D, Dunn G, Timothy K, Vincent GM, Lep- pert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704-706.
20. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Lep- part M. Linkage of the long QT syndrome to the Harvey ras-1 locus on chromosome 11. Am J Hum Genet. 1991;49:1335-1339.
21. Towbin JA, Pagotto L, Siu B, Robinson J, Moss AJ, McCabe ERB, Hejtmancik JF. Romano-Ward long QT syndrome (RWLQTS): evidence of genetic heterogeneity. Pediatr Res. 1992;31:23A. Abstract.
22. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the long QT syndrome gene. N Engi J Med. 1992;327:846-852.
23. Schwartz PJ. The longQT syndrome. In: Kulbertus HE, Wellens HJJ, eds. Sudden Death. The Hague: Martinus Nijhoff; 1980:358-378.
24. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J. 1986;112:61-64.
25. Davignon A, Rautaharju B, Boisselle E, Soumis F, Megelas M, Choquette A. Normal ECG standards for infants and children. Pediatr CardioL 1980;1:123-130.
26. Schwartz PJ, Malliani A. Electrical alternation of the T wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long QT syndrome. Am Heart J. 1975;89:45-50.
27. Smith JM, Clancy EA, Valeri CR, Ruskin JN, Cohen RJ. Electrical alternans and cardiac electrical instability. Circulation. 1988;77: 110-121.
28. Nearing BD, Huang AH, Verrier RL. Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave. Science. 1991;252:437-440.
KEY WoRDs llong QT syndrome * Current Perspectives
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arch 3, 2023
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