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Acetylcholine-lnduced prolongation of the qt interval in idiopathic long qt syndrome
sary to understand the mechanism responsible for the improvement in exercise-induced myocardial ischemia caused by the administration of ACE inhibitors to patients with microvascular angina. 1. Kemp HG. Left ventricular function in patients with the angina syndrome and normal coronary arteriograms. Am J Cardiol 1973;32:375-376. 2. Epstein SE. Cannon RO III. Site of increased resistance to coronary flow in patients with angina pectoris and normal epicardial coronary arteries. JAm Co11 Cardiol 1986;8:459-461. 3. Kaski JC, Rosano G, Gavrielides S, Chen L. Effects of angiotensin-converting enzyme inhIbition on exercise-induced angina and ST segment depression in patients with microvascular angina. JAm Cob Cardiol 1994:23:652-657. 4. Lindpaintner K, Ganten D. The cardiac renin-angiotensin system. Circ Res 1991;68:905-920. 5. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F. Corvol P. Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting ewyme gene
Acetylcholine-Induced in Idiopathic Yoshifusa
accounting for half the variance of serum ewyme levels. J C/in ~rwc.rt 1990; 86: I343- 1346. 6. Fowler h‘0. Holmes JC. Coronary and myocardial action of angiotensin. Circ Res 1964:14:191~201. 7. Egashira K, Inou T, Hirooka Y. Yamada A. Uwbe Y, Takerluta A. Evidence of impaired endothelium-dependent coronq vasodilatation in patients with ngina pectons and normal coronary angiogmms. N Erq/ J Med 1993;328: 1659- l&4. 8. Cambien F. Poirier 0, Lecerf L, Evans A, Cambou JP, Arveiler D. Luc G. Bard JM. Bara L, Ricard S, Tiret L. Amouyel P. Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme 1s a potent risk factor for myocardial infarction. Nurture1992:359:641-644. 9. Lindpaintner K, Pfeffer MA. Kreutr R, Stampfer MJ. Grodvtein F Lamotte F. Buring J, Hennekens CH. A prospectiw evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of iszhemic heart diseare. h’ Engl J Med 1995:332:706-71 I. 10. LachuriC ML, Ariri M, Guyene T-T, Alhenc-Gelas F, Menard J. Angiotensin converting enzyme gene polymorphism ha\ no influence on the c,rculating renin-angiotensin-aldosterone system or blood pressure in normotenaive wbjects. Circulation 1995:91:2933-2942.
Prolongation of the Long QT Syndrome
QT Interval
Aizawa, MD, Takashi Washizuka, MD, Yutaka Igarashi, MD, Hitoshi Kitazawa, Masaomi Chinushi, MD, Akira Abe, MD, and Akira Shibata, MD
MD,
he pathogenic mechanism of the congenital QT T prolongation remains to be determined.‘-” The imbalance of the sympathetic innervation of the heart
tients had syncopal episodes and were admitted on an emergency basis. Polymorphic VT or torsades de pointes was recorded in 3 female patients and frehas been shown to prolong the QT interval,2*3.6 and quent ventricular premature beats in 1 man on the the beneficial effect of ,&adrenergic blockade and following day of the syncopal episode. The remainleft stellate ganglionectomy in patients with congening 1 male patient was asymptomatic. ital long QT syndrome may provide evidence of the The prolonged QT interval was found in family role of the sympathetic activity.““” However, the fact members of 2 patients, but family members were not that deflections of humps in the monophasic action examined in the other 3 patients and electrocardiopotential, which are considered consistent with early grams were not available. A family history of sudden are increased by adrenergic death was found in 3 patients. A congenital hearing afterdepolarization, stimulig-‘2 suggests that the sympathetic nerve activ- disturbance was not observed in any family member ities are important as precipitating factors of lethal of the 5 patients. arrhythmia, as already reported by Schwartz et aL2,’ The electrocardiogram on admission was normal An abnormality in the regulation of the repolarizaexcept for a long QT interval: The corrected QT intion of the ventricular myocardium has been reported terval (QTc) I9 was >0.480 second”’ in all pa.tients. as a cause of the long QT syndrome3,‘3 and genetic No patient had been treated with drugs that are studies have provided evidence of abnormal known to prolong the QT interval. Blood chemistry and other routine blood examinations were normal. genes.14-” showed a normal heart. After treating a patient with Romano-Ward syn- Routine echocardiography drome in which QT prolongation and torsades de Exercise test results on the treadmill were negative for ischemic changes and no ventricular arrhythmia pointes were unexpectedly induced by intracoronary was induced. acetylcholine, ‘* the effect of intracoronary acetylIn the first patient, coronary arteriography was choline on the QT interval was studied in 4 subsequent patients with congenital or sporadic long QT performed to exclude ischemia as the cause of the interval and new insight into the underlying mech- ST-T changes, but it showed normal coronary arteries. Unexpectedly, a prolongation of the QT interval anism was provided. . .. and torsades de pointes were observed at the end of administration.18 After Three female and 2 male patients who had long intracoronary acetylcholine QT intervals were studied. The ages ranged from 18 the procedures were explained and patients gave into 75 years (mean 53 2 21) , and the prolonged QT formed consent, coronary arteriography was perinterval had been noted for 5 to 21 years. Four pa- formed in 4 subseqeunt patients. After confirmation of normal coronary arteries, acetylcholine diluted in normal saline solution was injected into the 1e:ft corFrom The First Department of Internal Medicine, Niigata Universiv onary artery at increasing doses: 25. 50, and 100 yg. School of Medrcine, Asahimachi, Nilgata 9.5 1, Japan. Dr Aizawa’s The administration of acetylcholine was repeated afaddress is’ the First Department of Internal Medicine, Asahimachl, ter the QT interval returned to the baseline level. In Niigata 95 1 , Japan Manuscript received August 2, 1995; revised 1 patient, the effect of acetylcholine was compared manuscript received October 24, 1995, and accepted October 26. BRIEF
REPORTS
879
second
0.6
0.2 0 Patiftnts 0 Con1rol
I ACh
Basal
Ach
(100
p g)
FIGURE 2. Acetylcholine (Ach]-induced change in the QT interval. The QT interval was prolonged in patients with kg QT syndrome, from 0.496 + 0.054 to 0.644 2 0.101 second (p eO.01) at 100 m of intracoronary ocetylcholine. In the control group, no change was observed: 0.388 + 0.037 versus 0.389 k 0.035 second. The sinus mte showed no significant change in the 2 groups, and the corrected QT interval showed a similar si nificant change. The QT interval was not prolonged by the ve 8. I& (not shown).
and the peak effect of acetylcholine on the QT interval was obtained. Blood pressure was continuously monitored during the study. Before coronary arteriography, electrophysiologic study was performed in a standardized manner 2o Programmed stimulation was attempted at the high right atrium and ventricles, but no arrhythmia was induced. The effective refractory period at the apex of the right ventricle was prolonged: 298 + 15 ms and 270 + 12 ms at basic cycle lengths of 600 and 400 ms, respectively. As the control group, 10 subjects, (5 men and 5 women, mean age 5 1 + 9 years [range 36 to 701) who underwent a provocation test to exclude coronary artery spasm as the cause of unexplained syn-
FIGURE 1. Change in the QT interval with acetylchdine (ACh). In control subiects (Control), the QT interval was 0.54 second, then prolonged to 0.72 second at the end of acetykholine administration (50 pg), and further prolonged to 0.82 second. There was a change in the T-U wave. The sinus cycb len rh showed lithe change (0.14 to 1.17 and 1.08 second), an 9 bmdycardia was not the cause of the QT prolongation.
before and after administration of 0.5 mg of intravenous atropine. The effect of the vehicle, normal saline, on the QT interval was also determined by intravenous injection. A 6- or 12-lead electrocardiogram was continuously recorded during each injection of acetylcholine TABLE I Response
of Sinus Cycle
Length,
QT Interval,
and Blood Pressure
Spont. CL (ms] Patient
Age (yr) and Sex
C
ACh
18M 50 M 60 F 60 F 75 F
860 1,000 770 850
820 1,000 830 850
1,110
1,050
898 k 128
888 % 94
I 2 3 A
5 Mean
+ SD
* p
880
THE AMERICAN
JOURNAL
OF CARDIOLOGY=’
Blood Pressure (sys./dio.) (mm bl
QTc (second”‘] Ath
C 0.539 0.500 0.525 0.480 0.550 0.519 k 0.029
Spont. CL = spontaneous
VOL.
77
C
0.683 0.620 0.657 0.680 0.799 0.688 k 0.067*
sinus cycle length;
APRIL 15,
1996
sys./dio.
ACh
104/65
108/64
164/76 147/66
160/72 142/77
160/86 192/72 153 ?I 32/73
= systolic/diasblic.
-+ 9
158/87 192/80 152 lr 32/76
k 9
TdP
1 .osec
FIGURE 3. QT prolongation and development of torsades de pointes (TdP). The QT interval was prolonged to >0.82 second with 100 pg of acetyicholine, and premature ventricular contraction occurred in bi eminy. After the long-short sequence, torsades de pointes occurred. Torsades de pointes was induced in 2 of 5 patients, but not in tf e control group.
cope, *’ but had negative
results, were included. Their electrocardiograms were normal, showing normal sinus rhythm and normal QTc interval (10.44 second 1’2). After confirmation of the absence of significant coronary artery disease, intracoronary administration of acetylcholine was begun in a manner similar to the patient group. The QT interval was serially measured during intracoronary acetylcholine administration usually in lead II or Vs. When the terminal of the T wave was not clear, other leads, such as Vi or V2, were used. Changes in the QT interval, heart rate, and blood pressure were noted at the end of acetylcholine administration, and peak values were compared in patients and control subjects. Statistically, paired or nonpaired t test was used for comparisons, and a p value 40.05 was considered as a significant difference. The coronary arteriograms were normal in all patients. The QT interval was 0.496 + 0.054 second in the basal state and showed a prolongation in the dose-dependent manner (Figure 1) . The peak value was 0.644 + 0.101 second with 100 pg of acetylcholine (Figure 2 and Table I). The corrected QT interval was prolonged from 0.5 19 + 0.029 to 0.688 -+ 0.067 second “2 (p +O.Ol ). The QT interval returned to the baseline level within 20 seconds after the end of acetylcholine administration. The electrocardiogram showed regular sinus rhythm until ventricular premature beats occurred (Figure 1) and the sinus cycle length showed no significant change: 898 2 128 versus 888 2 94 ms before and at the end of acetylcholine administration (Table I). Prolongation of the QT interval was not observed after adminstration of the vehicle (normal saline), and atropine attenuated the prolongation of the QT interval in 1 male patient (no. 2) : 0.62 versus 0.54 second.
In 2 women (nos. 1 and 3), torsades de pointes was initiated in association with prolongation of the QT interval (Figure 3). Before onset of torsades de pointes, no ST elevation was observed, and there were no complaints of chest pain. Blood pressure showed no change until torsades de pointes developed: 153 + 32/73 ? 9 versus 152 + 3 l/76 + 9 mm Hg (systolic/diastolic) before and after acetylcholine at 100 pg, respectively. When 100 pg of acetylcholine was administered to control subjects, the QT interval and QTc remained unchanged: 0.388 2 0.037 versus 0.1389 + 0.035 second (Figure 2) and 0.418 2 0.026 versus 0.401 k 0.024 second”‘. The sinus cycle length showed a nonsignificant change: 883 + 164 versus 934 2 196 ms. Blood pressure showed no change. At lower doses, no change was observed in the QT interval, heart rate, and blood pressure during acetylcholine administration. . . . The role of vagal activity in the long QT syndrome has been seldom studied thus far. Acetylcholine has been shown to prolong the action potential duration of the ventricular myocardium in sheep Purkinje fibers, 22,23 and vagal stimulation has been shown to prolong the refractory period in animals 24,25 or in human ventricles 26,27but, in the cesium-induced QT prolongation in rabbits, vagal stimulation has been shown to diminish early afterdepolarization and ventricular arrhythmias.28 The role of vagal nerve stimulation has not been settled in the long QT interval syndrome, and acetylcholine-induced prolongation of the QT interval of our first previous reportrs was an unexpected finding. Intracoronary acetylcholine was administered into the left coronary artery, and the acetylcholineinduced prolongation of the QT interval was observed in all patients with possibly congenital long BRIEF REPORT.5
881
QT interval syndrome, but not in the control group with normal QT intervals (Figure 2). Ventricular premature beats and torsades de pointes were induced at the time of the peak QT prolongation in 2 patients, but the QT interval was measured during regular sinus rhythm before ventricular arrhythmia occurred. Similarly, blood pressure showed no change until torsades de pointes deveioped in 2 patients. In these patients, bradycardia or adrenergic stimuli from a decrease in blood pressure was not the cause of the QT prolongation during intracoronary acetylcholine administration (Table I), and the nonspecific effect due to the vehicle was clearly excluded. The fact that atropine increased QT prolongation with acetylcholine may provide evidence that muscarinic receptors are involved; this should be tested in many patients. In conclusion, the following can he said from the present study: (1) Acetylcholine induced a prolongation of the QT interval only in patients with long QT syndrome. (2) Prolongation of the QT interval was reproducible and not due to a vehicle, hradycardia, or a decrease in blood pressure. (3) The mechanism of acetylcholine-caused prolongation of the QT interval is not known.
1. Romano C, Gemme G. Pongiglionr R. Aritomie cardiache rare dell’eta’ pediatrica. Clin Pedintr 1963;45:656-683. 2. Schwartz PI. Idiopathic long Q-T syndrome: progress and question. Am Heart J 1985;109.399-411. 3. Mosy AI. Schwartz PJ, Crampton RS. Locati F. Carleeb E. The long QT syndrome: a prospective international study. Cirtulutinn 1985;7 I: 17-21. 4. Jackman WM, Friday KJ, Anderson IL, Ahot EM, Clark M, Lazzwa R. The long QT syndrome: a critical review, new clinical observations and unifymg hypothesis. frog Curtlio~ax Dis 1988:31 :I 15-172. 5. Zipes DP. The long QT interval syndrome: a Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84:1414-1419. 6. Yanowitz F. Prestone JB. Abildskov JA. Functional distribution of right and left stellate mnervation to the ventricles: production of neurogenic electrocardmgraphic changes by unilateral alteration of sympathetic tone. Circ Res 1966;18:416-428. 7. Coyer BH. Pryor R, Kirsch WM. Blount SJ. Left stellectomy in the long QT syndrome. Chest 1978;74:584-586.
Value Echocardiography Bertrand
Cormier,
of Multiplane Transesophageal in Determining Aortic Valve Aortic Stenosis MD,
Bernard lung, MD, Jean-Marc Porte, and Alec Vahanian, MD
alculation of the aortic valve area in patients with aortic stenosis (AS) by transthoracic echocardiC ography using the continuity equation has been shown to be accurate when compared
with hemo-
From the De meni of Cardiolog Tenon Hospital, Paris, France Dr Cormier’s a cr dress IS. Department o y’, Cardlolqy, Tenon Hospital, 4, Rue de la Chine, 75020 Purls, France. Manuscript received August 7, 1995; revised manuscript received and accepted November 24 1995.
882
THE
AMERICAN
JOURNAL
8. Schwartz PJ, Locati EH, Moss AI, Crampton RS, Tlazzi R, Ruherti U. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome, A worldwide report. Circulation 1991;84:503-511. 9. Rosen MR. Wit AL. Triggered activity. In: Zipes DP, Rowlands DJ. eds. Progress in Cardiology. Philadelphia: Lea & Febiger, 1988:34-42. 10. Cranefield RF, Aronson RS. Cardiac arrhythmias: the role of triggered activity and other mechanisms. Mt Kisco, NY: Futara. 1966. 11. Bonatti V, Rolli A, Botti G. Recording of monophasic action potentials of the right ventricle in long QT syndromes complicated by severe ventricular arrhythmias. Eur Heorr J 1983;4:168179. 12. Shimizu W, Ohe T, Kurita T, Shimomura K. Early afterdepolarization induced by isoproterenol in patients with congenital long QT syndrome. Circulation 1990;84:19lS-1923. 13. Schwartz PJ, Locati EH, Napolitano C, Prior SG. The long QT syndrome, In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology. From Cell to Bedside. 2nd ed. Philadelphia: WB Saunders 1990:788-811, 14. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and Harvey ras-I gene. Science 1991:252:70&706. 15. Vincent BM. Hypothesis for the molecular physiology of the Romano-Ward long QT syndrome. J Am Cd Cm-did 1992:20:500-503. 16. Curran ME, Splawski I. Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995:80; I-20. 17. Wang Q, Shen G, Splawski I, Atkinson D, Li Z. Robinson JL, Moss Al, Towbin JA, Keating MT. SCNSA mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811. 18. AiLawa Y, Matsubam T, Higuchi K, Washizuka T, Tmura Y, Uchiyama H, Igarashi Y, Shibata A. Intrcoronary acetylcholine-induced prolongation of the QT interval and torsades de pointes in long QT Interval syndrome. Jpn Hean J 1994:35:683-688. 19. Bazett HC. Analysis of the time relationship of electrocardiograms. Hear? 1920;7:353-370. 20. Alzawa Y, Niwano S. Chinushi M, Naitoh N. Shrbata A. Incidence and mechanism of interruption of ventricular tachycardia with rapid ventricular pacing. Curularion 1002;82:589-595. 21. Igarashi Y, Yamazoe M, Suzuki K, Aizawa Y, Shibata A. Possible role of coronary spasm in unexplained syncope. Am J Cat-did 1990;65:713-712. 22. Lipsius SL, Gibbons WR. Acetylcholine lengthens action potentials of sheep cardiac Purkinje fibers. Am J Physiol 1980:238:H237-H243. 23. Carmeliet E, Ramon J. Electrophysiological effects of acetylcholine in sheep cardiac Purkinje fibers. P~Tuegers Arch 1980;387: l97-;!05. 24. Martins JB, Zlpes DP. Effects of sympathetic and vagal nerves on recovery properties of the endocardum and epicardium of the canine left ventricle. Circ Res 1980:36:100-I IO. 25. Takahashi N, Barber MJ, Zipes DP. Efferent vagal innervation of canine ventricle. Am J Physiol 1985;248:H89-H97. 26. Preystowsky EN, Jackman WM. Rinkenberger RI., Heger JJ, Zipes DP. Effect of autonomic blockade on ventricular refractoriwss and atrioventricular nodal conduction in humans. Circ Res 1981;49:51 I-518. 27. Shimizu W, Tsuchioka Y, Karasawa S, Nagam K, Mukai J, Yamagata T, Matsuura H, Kajlyama G, Matsuura Y. Differential effect of pharmacological autonomic blockade on some electrophysiological properties of the human ventricle and atrium. Br Heurl 3 1994:71:34-37. 28. Takahashi N. Ito M. Ishida S, Fujino T, Saikawa T, Atita M. Effects of vagal &nulation on c&urn-induced early afterdepolarization and ventricular arrhythmias in rabbits. Circulation 1992:86:19871992.
OF
CARDIOLOGY”
VOl
77
MD,
Area
Sophie Barbont,
in
MD,
dynamic measurements.132 Determination of left ventricular outflow tract diameter may be difficult in patients with a poor transthoracic window.3 The continuity equation is not valid in patients with subvalvular dynamic obstruction. Transesophageal echocardiography, in particular using a multiplane probe, has recently been proposed as an alternative to the continuity equation.” This study examines the clinical value of multiplane transesophageal echoAPRll
15,
1996
Acetylcholine-Induced in Idiopathic Yoshifusa
accounting for half the variance of serum ewyme levels. J C/in ~rwc.rt 1990; 86: I343- 1346. 6. Fowler h‘0. Holmes JC. Coronary and myocardial action of angiotensin. Circ Res 1964:14:191~201. 7. Egashira K, Inou T, Hirooka Y. Yamada A. Uwbe Y, Takerluta A. Evidence of impaired endothelium-dependent coronq vasodilatation in patients with ngina pectons and normal coronary angiogmms. N Erq/ J Med 1993;328: 1659- l&4. 8. Cambien F. Poirier 0, Lecerf L, Evans A, Cambou JP, Arveiler D. Luc G. Bard JM. Bara L, Ricard S, Tiret L. Amouyel P. Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme 1s a potent risk factor for myocardial infarction. Nurture1992:359:641-644. 9. Lindpaintner K, Pfeffer MA. Kreutr R, Stampfer MJ. Grodvtein F Lamotte F. Buring J, Hennekens CH. A prospectiw evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of iszhemic heart diseare. h’ Engl J Med 1995:332:706-71 I. 10. LachuriC ML, Ariri M, Guyene T-T, Alhenc-Gelas F, Menard J. Angiotensin converting enzyme gene polymorphism ha\ no influence on the c,rculating renin-angiotensin-aldosterone system or blood pressure in normotenaive wbjects. Circulation 1995:91:2933-2942.
Prolongation of the Long QT Syndrome
QT Interval
Aizawa, MD, Takashi Washizuka, MD, Yutaka Igarashi, MD, Hitoshi Kitazawa, Masaomi Chinushi, MD, Akira Abe, MD, and Akira Shibata, MD
MD,
he pathogenic mechanism of the congenital QT T prolongation remains to be determined.‘-” The imbalance of the sympathetic innervation of the heart
tients had syncopal episodes and were admitted on an emergency basis. Polymorphic VT or torsades de pointes was recorded in 3 female patients and frehas been shown to prolong the QT interval,2*3.6 and quent ventricular premature beats in 1 man on the the beneficial effect of ,&adrenergic blockade and following day of the syncopal episode. The remainleft stellate ganglionectomy in patients with congening 1 male patient was asymptomatic. ital long QT syndrome may provide evidence of the The prolonged QT interval was found in family role of the sympathetic activity.““” However, the fact members of 2 patients, but family members were not that deflections of humps in the monophasic action examined in the other 3 patients and electrocardiopotential, which are considered consistent with early grams were not available. A family history of sudden are increased by adrenergic death was found in 3 patients. A congenital hearing afterdepolarization, stimulig-‘2 suggests that the sympathetic nerve activ- disturbance was not observed in any family member ities are important as precipitating factors of lethal of the 5 patients. arrhythmia, as already reported by Schwartz et aL2,’ The electrocardiogram on admission was normal An abnormality in the regulation of the repolarizaexcept for a long QT interval: The corrected QT intion of the ventricular myocardium has been reported terval (QTc) I9 was >0.480 second”’ in all pa.tients. as a cause of the long QT syndrome3,‘3 and genetic No patient had been treated with drugs that are studies have provided evidence of abnormal known to prolong the QT interval. Blood chemistry and other routine blood examinations were normal. genes.14-” showed a normal heart. After treating a patient with Romano-Ward syn- Routine echocardiography drome in which QT prolongation and torsades de Exercise test results on the treadmill were negative for ischemic changes and no ventricular arrhythmia pointes were unexpectedly induced by intracoronary was induced. acetylcholine, ‘* the effect of intracoronary acetylIn the first patient, coronary arteriography was choline on the QT interval was studied in 4 subsequent patients with congenital or sporadic long QT performed to exclude ischemia as the cause of the interval and new insight into the underlying mech- ST-T changes, but it showed normal coronary arteries. Unexpectedly, a prolongation of the QT interval anism was provided. . .. and torsades de pointes were observed at the end of administration.18 After Three female and 2 male patients who had long intracoronary acetylcholine QT intervals were studied. The ages ranged from 18 the procedures were explained and patients gave into 75 years (mean 53 2 21) , and the prolonged QT formed consent, coronary arteriography was perinterval had been noted for 5 to 21 years. Four pa- formed in 4 subseqeunt patients. After confirmation of normal coronary arteries, acetylcholine diluted in normal saline solution was injected into the 1e:ft corFrom The First Department of Internal Medicine, Niigata Universiv onary artery at increasing doses: 25. 50, and 100 yg. School of Medrcine, Asahimachi, Nilgata 9.5 1, Japan. Dr Aizawa’s The administration of acetylcholine was repeated afaddress is’ the First Department of Internal Medicine, Asahimachl, ter the QT interval returned to the baseline level. In Niigata 95 1 , Japan Manuscript received August 2, 1995; revised 1 patient, the effect of acetylcholine was compared manuscript received October 24, 1995, and accepted October 26. BRIEF
REPORTS
879
second
0.6
0.2 0 Patiftnts 0 Con1rol
I ACh
Basal
Ach
(100
p g)
FIGURE 2. Acetylcholine (Ach]-induced change in the QT interval. The QT interval was prolonged in patients with kg QT syndrome, from 0.496 + 0.054 to 0.644 2 0.101 second (p eO.01) at 100 m of intracoronary ocetylcholine. In the control group, no change was observed: 0.388 + 0.037 versus 0.389 k 0.035 second. The sinus mte showed no significant change in the 2 groups, and the corrected QT interval showed a similar si nificant change. The QT interval was not prolonged by the ve 8. I& (not shown).
and the peak effect of acetylcholine on the QT interval was obtained. Blood pressure was continuously monitored during the study. Before coronary arteriography, electrophysiologic study was performed in a standardized manner 2o Programmed stimulation was attempted at the high right atrium and ventricles, but no arrhythmia was induced. The effective refractory period at the apex of the right ventricle was prolonged: 298 + 15 ms and 270 + 12 ms at basic cycle lengths of 600 and 400 ms, respectively. As the control group, 10 subjects, (5 men and 5 women, mean age 5 1 + 9 years [range 36 to 701) who underwent a provocation test to exclude coronary artery spasm as the cause of unexplained syn-
FIGURE 1. Change in the QT interval with acetylchdine (ACh). In control subiects (Control), the QT interval was 0.54 second, then prolonged to 0.72 second at the end of acetykholine administration (50 pg), and further prolonged to 0.82 second. There was a change in the T-U wave. The sinus cycb len rh showed lithe change (0.14 to 1.17 and 1.08 second), an 9 bmdycardia was not the cause of the QT prolongation.
before and after administration of 0.5 mg of intravenous atropine. The effect of the vehicle, normal saline, on the QT interval was also determined by intravenous injection. A 6- or 12-lead electrocardiogram was continuously recorded during each injection of acetylcholine TABLE I Response
of Sinus Cycle
Length,
QT Interval,
and Blood Pressure
Spont. CL (ms] Patient
Age (yr) and Sex
C
ACh
18M 50 M 60 F 60 F 75 F
860 1,000 770 850
820 1,000 830 850
1,110
1,050
898 k 128
888 % 94
I 2 3 A
5 Mean
+ SD
* p
880
THE AMERICAN
JOURNAL
OF CARDIOLOGY=’
Blood Pressure (sys./dio.) (mm bl
QTc (second”‘] Ath
C 0.539 0.500 0.525 0.480 0.550 0.519 k 0.029
Spont. CL = spontaneous
VOL.
77
C
0.683 0.620 0.657 0.680 0.799 0.688 k 0.067*
sinus cycle length;
APRIL 15,
1996
sys./dio.
ACh
104/65
108/64
164/76 147/66
160/72 142/77
160/86 192/72 153 ?I 32/73
= systolic/diasblic.
-+ 9
158/87 192/80 152 lr 32/76
k 9
TdP
1 .osec
FIGURE 3. QT prolongation and development of torsades de pointes (TdP). The QT interval was prolonged to >0.82 second with 100 pg of acetyicholine, and premature ventricular contraction occurred in bi eminy. After the long-short sequence, torsades de pointes occurred. Torsades de pointes was induced in 2 of 5 patients, but not in tf e control group.
cope, *’ but had negative
results, were included. Their electrocardiograms were normal, showing normal sinus rhythm and normal QTc interval (10.44 second 1’2). After confirmation of the absence of significant coronary artery disease, intracoronary administration of acetylcholine was begun in a manner similar to the patient group. The QT interval was serially measured during intracoronary acetylcholine administration usually in lead II or Vs. When the terminal of the T wave was not clear, other leads, such as Vi or V2, were used. Changes in the QT interval, heart rate, and blood pressure were noted at the end of acetylcholine administration, and peak values were compared in patients and control subjects. Statistically, paired or nonpaired t test was used for comparisons, and a p value 40.05 was considered as a significant difference. The coronary arteriograms were normal in all patients. The QT interval was 0.496 + 0.054 second in the basal state and showed a prolongation in the dose-dependent manner (Figure 1) . The peak value was 0.644 + 0.101 second with 100 pg of acetylcholine (Figure 2 and Table I). The corrected QT interval was prolonged from 0.5 19 + 0.029 to 0.688 -+ 0.067 second “2 (p +O.Ol ). The QT interval returned to the baseline level within 20 seconds after the end of acetylcholine administration. The electrocardiogram showed regular sinus rhythm until ventricular premature beats occurred (Figure 1) and the sinus cycle length showed no significant change: 898 2 128 versus 888 2 94 ms before and at the end of acetylcholine administration (Table I). Prolongation of the QT interval was not observed after adminstration of the vehicle (normal saline), and atropine attenuated the prolongation of the QT interval in 1 male patient (no. 2) : 0.62 versus 0.54 second.
In 2 women (nos. 1 and 3), torsades de pointes was initiated in association with prolongation of the QT interval (Figure 3). Before onset of torsades de pointes, no ST elevation was observed, and there were no complaints of chest pain. Blood pressure showed no change until torsades de pointes developed: 153 + 32/73 ? 9 versus 152 + 3 l/76 + 9 mm Hg (systolic/diastolic) before and after acetylcholine at 100 pg, respectively. When 100 pg of acetylcholine was administered to control subjects, the QT interval and QTc remained unchanged: 0.388 2 0.037 versus 0.1389 + 0.035 second (Figure 2) and 0.418 2 0.026 versus 0.401 k 0.024 second”‘. The sinus cycle length showed a nonsignificant change: 883 + 164 versus 934 2 196 ms. Blood pressure showed no change. At lower doses, no change was observed in the QT interval, heart rate, and blood pressure during acetylcholine administration. . . . The role of vagal activity in the long QT syndrome has been seldom studied thus far. Acetylcholine has been shown to prolong the action potential duration of the ventricular myocardium in sheep Purkinje fibers, 22,23 and vagal stimulation has been shown to prolong the refractory period in animals 24,25 or in human ventricles 26,27but, in the cesium-induced QT prolongation in rabbits, vagal stimulation has been shown to diminish early afterdepolarization and ventricular arrhythmias.28 The role of vagal nerve stimulation has not been settled in the long QT interval syndrome, and acetylcholine-induced prolongation of the QT interval of our first previous reportrs was an unexpected finding. Intracoronary acetylcholine was administered into the left coronary artery, and the acetylcholineinduced prolongation of the QT interval was observed in all patients with possibly congenital long BRIEF REPORT.5
881
QT interval syndrome, but not in the control group with normal QT intervals (Figure 2). Ventricular premature beats and torsades de pointes were induced at the time of the peak QT prolongation in 2 patients, but the QT interval was measured during regular sinus rhythm before ventricular arrhythmia occurred. Similarly, blood pressure showed no change until torsades de pointes deveioped in 2 patients. In these patients, bradycardia or adrenergic stimuli from a decrease in blood pressure was not the cause of the QT prolongation during intracoronary acetylcholine administration (Table I), and the nonspecific effect due to the vehicle was clearly excluded. The fact that atropine increased QT prolongation with acetylcholine may provide evidence that muscarinic receptors are involved; this should be tested in many patients. In conclusion, the following can he said from the present study: (1) Acetylcholine induced a prolongation of the QT interval only in patients with long QT syndrome. (2) Prolongation of the QT interval was reproducible and not due to a vehicle, hradycardia, or a decrease in blood pressure. (3) The mechanism of acetylcholine-caused prolongation of the QT interval is not known.
1. Romano C, Gemme G. Pongiglionr R. Aritomie cardiache rare dell’eta’ pediatrica. Clin Pedintr 1963;45:656-683. 2. Schwartz PI. Idiopathic long Q-T syndrome: progress and question. Am Heart J 1985;109.399-411. 3. Mosy AI. Schwartz PJ, Crampton RS. Locati F. Carleeb E. The long QT syndrome: a prospective international study. Cirtulutinn 1985;7 I: 17-21. 4. Jackman WM, Friday KJ, Anderson IL, Ahot EM, Clark M, Lazzwa R. The long QT syndrome: a critical review, new clinical observations and unifymg hypothesis. frog Curtlio~ax Dis 1988:31 :I 15-172. 5. Zipes DP. The long QT interval syndrome: a Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84:1414-1419. 6. Yanowitz F. Prestone JB. Abildskov JA. Functional distribution of right and left stellate mnervation to the ventricles: production of neurogenic electrocardmgraphic changes by unilateral alteration of sympathetic tone. Circ Res 1966;18:416-428. 7. Coyer BH. Pryor R, Kirsch WM. Blount SJ. Left stellectomy in the long QT syndrome. Chest 1978;74:584-586.
Value Echocardiography Bertrand
Cormier,
of Multiplane Transesophageal in Determining Aortic Valve Aortic Stenosis MD,
Bernard lung, MD, Jean-Marc Porte, and Alec Vahanian, MD
alculation of the aortic valve area in patients with aortic stenosis (AS) by transthoracic echocardiC ography using the continuity equation has been shown to be accurate when compared
with hemo-
From the De meni of Cardiolog Tenon Hospital, Paris, France Dr Cormier’s a cr dress IS. Department o y’, Cardlolqy, Tenon Hospital, 4, Rue de la Chine, 75020 Purls, France. Manuscript received August 7, 1995; revised manuscript received and accepted November 24 1995.
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8. Schwartz PJ, Locati EH, Moss AI, Crampton RS, Tlazzi R, Ruherti U. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome, A worldwide report. Circulation 1991;84:503-511. 9. Rosen MR. Wit AL. Triggered activity. In: Zipes DP, Rowlands DJ. eds. Progress in Cardiology. Philadelphia: Lea & Febiger, 1988:34-42. 10. Cranefield RF, Aronson RS. Cardiac arrhythmias: the role of triggered activity and other mechanisms. Mt Kisco, NY: Futara. 1966. 11. Bonatti V, Rolli A, Botti G. Recording of monophasic action potentials of the right ventricle in long QT syndromes complicated by severe ventricular arrhythmias. Eur Heorr J 1983;4:168179. 12. Shimizu W, Ohe T, Kurita T, Shimomura K. Early afterdepolarization induced by isoproterenol in patients with congenital long QT syndrome. Circulation 1990;84:19lS-1923. 13. Schwartz PJ, Locati EH, Napolitano C, Prior SG. The long QT syndrome, In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology. From Cell to Bedside. 2nd ed. Philadelphia: WB Saunders 1990:788-811, 14. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and Harvey ras-I gene. Science 1991:252:70&706. 15. Vincent BM. Hypothesis for the molecular physiology of the Romano-Ward long QT syndrome. J Am Cd Cm-did 1992:20:500-503. 16. Curran ME, Splawski I. Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995:80; I-20. 17. Wang Q, Shen G, Splawski I, Atkinson D, Li Z. Robinson JL, Moss Al, Towbin JA, Keating MT. SCNSA mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811. 18. AiLawa Y, Matsubam T, Higuchi K, Washizuka T, Tmura Y, Uchiyama H, Igarashi Y, Shibata A. Intrcoronary acetylcholine-induced prolongation of the QT interval and torsades de pointes in long QT Interval syndrome. Jpn Hean J 1994:35:683-688. 19. Bazett HC. Analysis of the time relationship of electrocardiograms. Hear? 1920;7:353-370. 20. Alzawa Y, Niwano S. Chinushi M, Naitoh N. Shrbata A. Incidence and mechanism of interruption of ventricular tachycardia with rapid ventricular pacing. Curularion 1002;82:589-595. 21. Igarashi Y, Yamazoe M, Suzuki K, Aizawa Y, Shibata A. Possible role of coronary spasm in unexplained syncope. Am J Cat-did 1990;65:713-712. 22. Lipsius SL, Gibbons WR. Acetylcholine lengthens action potentials of sheep cardiac Purkinje fibers. Am J Physiol 1980:238:H237-H243. 23. Carmeliet E, Ramon J. Electrophysiological effects of acetylcholine in sheep cardiac Purkinje fibers. P~Tuegers Arch 1980;387: l97-;!05. 24. Martins JB, Zlpes DP. Effects of sympathetic and vagal nerves on recovery properties of the endocardum and epicardium of the canine left ventricle. Circ Res 1980:36:100-I IO. 25. Takahashi N, Barber MJ, Zipes DP. Efferent vagal innervation of canine ventricle. Am J Physiol 1985;248:H89-H97. 26. Preystowsky EN, Jackman WM. Rinkenberger RI., Heger JJ, Zipes DP. Effect of autonomic blockade on ventricular refractoriwss and atrioventricular nodal conduction in humans. Circ Res 1981;49:51 I-518. 27. Shimizu W, Tsuchioka Y, Karasawa S, Nagam K, Mukai J, Yamagata T, Matsuura H, Kajlyama G, Matsuura Y. Differential effect of pharmacological autonomic blockade on some electrophysiological properties of the human ventricle and atrium. Br Heurl 3 1994:71:34-37. 28. Takahashi N. Ito M. Ishida S, Fujino T, Saikawa T, Atita M. Effects of vagal &nulation on c&urn-induced early afterdepolarization and ventricular arrhythmias in rabbits. Circulation 1992:86:19871992.
OF
CARDIOLOGY”
VOl
77
MD,
Area
Sophie Barbont,
in
MD,
dynamic measurements.132 Determination of left ventricular outflow tract diameter may be difficult in patients with a poor transthoracic window.3 The continuity equation is not valid in patients with subvalvular dynamic obstruction. Transesophageal echocardiography, in particular using a multiplane probe, has recently been proposed as an alternative to the continuity equation.” This study examines the clinical value of multiplane transesophageal echoAPRll
15,
1996