- Email: [email protected]
Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation
A, Fox K. Circadian variation of total ischemic burden and its alteration with anti-anginal agents. Lancet 1988;2:755–759. 10. Rostagno C, Taddei T, Paladini B, Modesti PA, Utari P, Bertini G. The onset of symptomatic atrial fibrillation and paroxysmal supraventricular tachycardia is characterized by different circadian rhythms. Am J Cardiol 1993;71:453– 455. 11. Clair WK, Wilkinson WE, McCarthy EA, Page RL, Pritchett ELC. Spontaneous occurrence of symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia in untreated patients. Circulation 1993;87:1114 – 1122. 12. Yamashita T, Murakawa Y, Sezaki K, Inoue M, Hayami N, Shuzui Y, Omata M. Circadian variation of paroxysmal atrial fibrillation. Circulation 1997;96: 1537–1541. 13. Sopher SM, Hnatkova K, Waktare JEP, Murgatroyd FD, Camm AJ, Malik M. Circadian variation in atrial fibrillation in patients with frequent paroxysms. PACE 1998;21:2445–2449. 14. Kupari M, Koskinen P, Lenonen H. Double-peaking circadian variation in the occurrence of sustained supraventricular tachyarrhythmias. Am Heart J 1990; 120:1364 –1369.
15. Viskin S, Golovner M, Malov N, Fish R, Alroy I, Vila Y, Laniado S, Kaplinsky E, Roth A. Circadian variation of symptomatic paroxysmal atrial fibrillation. Data from almost 10,000 episodes. Eur Heart J 1999;20:1429 –1434. 16. Attuel P, Pellerin D, Mugica J, Coumel P. DDD pacing: an effective treatment modality for recurrent atrial arrhythmias. PACE 1988;11:1647– 654. 17. Gillis AM, Wyse DG, Connolly ST, Dubuc M, Philippon F, Yee R, Lacombe P, Rose MS, Kerr CD. Atrial pacing periablation for prevention of paroxysmal atrial fibrillation. Circulation 1999;99:2553–2558. 18. Gillis AM, for the PA3 Study Investigators. The Atrial Pacing Peri-Ablation for Paroxysmal Atrial Fibrillation (PA3) Study rationale and study program. Europace 1999;1:40 – 42. 19. Fitts SM, Hill MRS, Mehra R, Gillis AM. High rate atrial tachyarrhythmia detections in implantable pulse generators: low incidence of false positive detections. PACE 2000;23:1080 –1086. 20. Motulsky HJ, Searle P. Interpreting nonlinear regression results. In: Graph Pad Prism Version 2.0 User’s Manual. San Diego, CA: Graph Pad Software, Inc., 1994:267–283.
Usefulness of Handgrip to Improve Ibutilide Efficacy in Organizing Atrial Electrical Activity During Atrial Fibrillation Maria Vittoria Pitzalis, MD, PhD, Massimo Grimaldi, MD, Matteo Anaclerio, MD, Massimo Iacoviello, MD, Giovanni Luzzi, MD, Cinzia Forleo, MD, and Paolo Rizzon, herapeutic strategies aimed at terminating arrhythmias are successful when they modify the mechT anisms responsible for the maintenance of the arrhythmia. The persistence of atrial fibrillation (AF) seems to depend on a critical number of wavelets depending on the size of the atrium and circuit.1,2 The wavelength is the fundamental parameter determining the size of the circuit, and depends on conduction velocity and the refractory period: when one of these variables increases, the size of the circuit increases, thus leading to a reduction in the number of circuits and favoring termination of AF. The prolongation of the refractory period, such as that obtained by class 3 antiarrhythmic drugs, has a success rate in restoring sinus rhythm of 20% to 50%.3–5 The simultaneous increase in conduction velocity could increase this percentage. Although no drugs are currently available for this purpose, it is possible that the increased adrenergic activity induced by isometric exercise6 enhances conduction velocity,7,8 leading to an organization of atrial activity. The present study sought to analyze the effect of isometric exercise (alone and in association with ibutilide infusion) on atrial electrical activity during AF. •••
Fifteen consecutive patients with persistent AF requiring internal electrical conversion to sinus rhythm gave their informed consent to participate in the study, which was approved by our local ethics committee. All patients were receiving optimal anticoagulant therapy at the time of the study and any antiarrhythmic drug previously taken had been discontinued for at From the Institute of Cardiology, University of Bari, Bari, Italy. Dr. Pitzalis’ address is: Institute of Cardiology–University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail: mariavittoria. [email protected]. Manuscript received August 14, 2000; revised manuscript received and accepted September 25, 2000.
798
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 March 15, 2001
MD
TABLE 1 Clinical Characteristics of Study Patients Age (yrs) Men/women Weight (kg) Height (cm) Left ventricular ejection fraction (%) Left atrial diameter (mm) Left atrial diameter during handgrip (mm) Underlying heart disease (no.) Systemic hypertension Valvular disease Coronary heart disease Hypertrophic cardiomyopathy Idiopathic dilated cardiomyopathy Concomitant medication (no.) Digoxin -blockers ACE inhibitors Calcium antagonists Diuretics
63 ⫾ 11 11/4 78 ⫾ 13 168 ⫾ 8 57 ⫾ 8 41 ⫾ 4 40 ⫾ 5 12 6 3 1 1 1 12 4 0 4 5 3
Values are expressed as mean ⫾ SD or number of patients. ACE ⫽ angiotensin-converting enzyme.
least 5 half-lives; none had an external cardioversion failure. In the morning, in a fasting state, all patients had 1 bipolar catheter placed in the right ventricular apex (for ventricular sensing and pacing), and 2 multipolar temporary EP-defibrillation catheters positioned in the high right atrium (VascoStim TC 2 ⫹1 CK, InControl, Weil am Rhein, Germany) and in the distal coronary sinus (VascoStim TC 3 ⫹1 DT, InControl) to record right and left atrial electrical activity. The study protocol consisted of 4 evaluations: under baseline conditions (10 minutes), after saline infusion (20 ml in 10 minutes), a first ibutilide infusion (0.87 mg or 0.01 mg/kg diluted with saline to 20 ml in 10 minutes if the patient weighed ⬍60 kg) started 10 minutes after the end of the saline infusion, 0002-9149/01/$–see front matter PII S0002-9149(00)01510-1
TABLE 2 Effects of Handgrip on Electrophysiologic and Hemodynamic Parameters Recorded Two Minutes After Saline and Ibutilide Infusions and During Handgrip Variable RA (ms) CS (ms) Heart rate (beats/min) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
Saline (n ⫽ 15) 141 139 94 131 85
⫾ ⫾ ⫾ ⫾ ⫾
29 29 18 18 7
Handgrip (n ⫽ 15) 171 165 112 157 106
⫾ ⫾ ⫾ ⫾ ⫾
24* 29† 22* 26* 10*
Ibutilide 1 (n ⫽ 13) 197 188 97 132 86
⫾ ⫾ ⫾ ⫾ ⫾
43 34 14 15 6
Handgrip (n ⫽ 13) 221 211 116 159 108
⫾ ⫾ ⫾ ⫾ ⫾
39928 40‡ 19* 24† 7*
Ibutilide 2 (n ⫽ 10) 226 215 90 132 85
⫾ ⫾ ⫾ ⫾ ⫾
48 56 14 16 7
Handgrip (n ⫽ 9) 257 246 113 155 109
⫾ ⫾ ⫾ ⫾ ⫾
69‡ 67§ 18† 22‡ 7‡
*p ⬍0.001 versus preceding phase; †p ⬍0.002 versus preceding phase; ‡p ⬍0.005 versus preceding phase; §p ⬍0.01 versus preceding phase. CS ⫽ mean atrial cycle length recorded at the level of distal coronary sinus; RA ⫽ mean atrial cycle length recorded at the level of high right atrium.
FIGURE 1. Surface electrograms recorded in lead DII, right atrial activity recorded in the high right atrium (HRA), and left atrial activity recorded in the distal coronary sinus (DCS) are shown. A, electrical activity recorded after saline infusion; B, activity recorded during handgrip, which caused organization of atrial electrical activity.
and a second ibutilide infusion started 10 minutes after the end of the first. Five minutes after the end of each of these evaluations, a handgrip test was performed using a standard device (Martin Vigormeter, Germany) on the dominant hand at 100% maximum voluntary grip strength for 15 seconds; this test was aided by a visual feedback of the force output. Electrograms were recorded throughout all phases by means of a polygraph (Bard Lab System, Lowell, Massachusetts),
and those recorded 2 minutes after each infusion and during the maximum handgrip were analyzed. Mean atrial cycle length was calculated for each phase by measuring manually all atrial cycles recorded over 10 seconds (from the fifth to the 15 second in the case of handgrip); during the same periods, mean ventricular rate was calculated. Arterial blood pressure was measured by sphygmanometer during each evaluation. In case any of the interventions led to sinus rhythm BRIEF REPORTS
799
FIGURE 2. Surface electrograms recorded in lead DII, right atrial activity recorded in the high right atrium (HRA), and left atrial activity recorded in the distal coronary sinus (DCS) are shown. A, electrical activity recorded after the second ibutilide infusion; B, activity recorded during handgrip, which caused further organization of atrial electrical activity and restoration of sinus rhythm.
restoration, the protocol was stopped; otherwise patients underwent electrical cardioversion. Before the procedure, 2-dimensional and M-mode echocardiographic measurements of the left atrial diameter during either baseline and maximum handgrip for 15 seconds were obtained (Hewlett-Packard, model 77765A, Palo Alto, California) in all patients in the left lateral recumbent position using the standard parasternal, long-axis view.9 The recordings were analyzed off-line by 2 blinded observers and measurements were averaged over at least 5 cardiac cycles. Data were analyzed using Statistica 5.0 for Windows 95 (StatSoft Inc., Tulsa, Oklahoma), and results compared using Wilcoxon’s test. A p value ⬍0.05 was considered statistically significant. Clinical characteristics of the patients are listed in Table 1. AF lasted for a median period of 66 days (range 22 to 270). The handgrip performed before the procedure, during echocardiographic evaluation, did not cause any significant modification in the left atrial diameter (Table 1), and was not associated with sinus rhythm restoration. The electrophysiologic and hemodynamic characteristics observed during the different 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 87
phases of the study are listed in Table 2. When all patients were considered as a whole, the value of mean atrial cycle length recorded in the right atrium did not differ from that found in the left atrium. There was no statistically significant difference between the values recorded at baseline and those recorded during saline infusion. The first ibutilide infusion led to an increase in the mean atrial cycle length compared with saline: ⫹39.7% in the right atrium (p ⬍0.001) and ⫹35.3% in the left atrium (p ⬍0.001), with evident organization of left and right atrial electrical activity. The second ibutilide infusion was associated with a further increase in mean atrial cycle length: ⫹14.7% in the right atrium (p ⬍0.005) and ⫹14.4% in the left atrium (p ⬍0.005). In all patients, maximum effort significantly increased systolic blood pressure, mean ventricular rate, and mean atrial cycle length (Table 2). Prolongation of atrial cycle length was immediately evident at the beginning of handgrip and was observed in all patients in both the right and left atria compared with each preceding condition (i.e., baseline, ⫹29.3% in the right atrium and ⫹21% in the left atrium; saline infusion, ⫹21.3% in the right atrium MARCH 15, 2001
and ⫹18.7% in the left atrium [Figure 1]; first ibutilide infusion, ⫹12.2% in the right and left atria; and second ibutilide infusion, ⫹13.7% in the right atrium and ⫹14.4% in the left atrium [Figure 2]). Sinus rhythm was restored in 10 of the 15 patients (66.7%) during the procedure: 2 after the first ibutilide infusion, 4 after the second, and 4 during the 15 seconds of maximal handgrip (1 at the 11th second of maximum handgrip after the first ibutilide infusion, and 3 at the third, ninth, and 15th second after the second ibutilide infusion). •••
The main finding of this study is that handgrip organizes atrial electrical activity during AF, thus improving our understanding of how to modify the electrophysiologic substrate of this arrhythmia and offering a new method for enhancing the cardioversion rate. Handgrip evokes an increase in sympathetic activity which, on the basis of our results, interacts with the mechanisms responsible for the maintenance of AF. According to the model suggested by Moe et al1 and Alessie,2 circuit size is of fundamental importance in favoring the maintenance of the arrhythmia; prolonging the atrial refractory period and enhancing conduction velocity are thought to favor restoration of sinus rhythm. Class III antiarrhythmic drugs are efficacious because they prolong refractoriness, an effect that was confirmed in this study by the fact that ibutilide significantly increased the mean atrial cycle length and thus led to the organization of atrial activity. However, ibutilide affects only one of the parameters considered to be critical in maintaining the arrhythmia. The only known way of enhancing conduction velocity is to increase adrenergic activity through an increase in the cyclic adenosine monophosphate levels.7,8 Handgrip is a safe and noninvasive method of increasing adrenergic activity,6 and causes a significant increase in mean atrial cycle length. This effect was clear whether the exercise was performed after saline or ibutilide infusion, but the fact that it was greatest when associated with ibutilide suggests that the 2 interventions
act differently in organizing atrial activity (1 on the refractory period, the other on conduction velocity) and thus have an additive effect. The efficacy of handgrip may also be due to its ability to reduce atrial dimension by increasing either atrial contractility10 or intrathoracic pressure, and thus reducing venous return.1,2 However, in our series, handgrip did not change left atrial diameter; therefore, the organization of AF caused by handgrip is mainly the result of enhancement in conduction velocity. In conclusion, this study shows that handgrip (alone and associated with ibutilide) can favorably modify the electrophysiologic properties of the atria during AF. These results shed new light on the possibility of enhancing the AF conversion rate by combining drugs and maneuvers that selectively act on the pathophysiologic mechanisms of AF. 1. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964;67:200 –220. 2. Alessie MA. Reentrant mechanisms underlying atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Toronto, Canada: WB Saunders, 1995:562–566. 3. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation. Circulation 1997;96:4298 – 4306. 4. Volgman AS, Carberry PA, Stambler B, Lewis WR, Dunn GH, Perry KT, Vanderlugt JT, Kowey PR. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol 1998;31:1414 –1419. 5. Vos MA, Golitsyn SR, Stangl K, Ruda MY, Van Wijk LV, Harry JD, Perry KT, Touboul P, Steinbeck G, Wellens HJ. Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998;79:568 –575. 6. Martin CE, Shaver JA, Leon DF, Thompson ME, Reddy PS, Leonard JJ. Autonomic mechanisms in hemodynamic responses to isometric exercise. J Clin Invest 1974;54:104 –115. 7. Burt JM, Spray DC. Inotropic agents modulate gap junctional conductance between cardiac myocytes. Am J Physiol 1988;254:H1206 –H1210. 8. van Rijen HVM, van Veen TAB, Hermans MMP, Jongsma HJ. Human connexin40 gap junction channels are modulated by cAMP. Cardiovasc Res 2000;45:941–951. 9. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 10. Schafers RF, Adler S, Daul A, Zeitler G, Vogelsang M, Zerkowski HR, Brodde OE. Positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in the human heart: effects of long-term beta 1-adrenoceptor antagonist treatment. J Am Coll Cardiol 1994;23:1224 –33.
BRIEF REPORTS
801
15. Viskin S, Golovner M, Malov N, Fish R, Alroy I, Vila Y, Laniado S, Kaplinsky E, Roth A. Circadian variation of symptomatic paroxysmal atrial fibrillation. Data from almost 10,000 episodes. Eur Heart J 1999;20:1429 –1434. 16. Attuel P, Pellerin D, Mugica J, Coumel P. DDD pacing: an effective treatment modality for recurrent atrial arrhythmias. PACE 1988;11:1647– 654. 17. Gillis AM, Wyse DG, Connolly ST, Dubuc M, Philippon F, Yee R, Lacombe P, Rose MS, Kerr CD. Atrial pacing periablation for prevention of paroxysmal atrial fibrillation. Circulation 1999;99:2553–2558. 18. Gillis AM, for the PA3 Study Investigators. The Atrial Pacing Peri-Ablation for Paroxysmal Atrial Fibrillation (PA3) Study rationale and study program. Europace 1999;1:40 – 42. 19. Fitts SM, Hill MRS, Mehra R, Gillis AM. High rate atrial tachyarrhythmia detections in implantable pulse generators: low incidence of false positive detections. PACE 2000;23:1080 –1086. 20. Motulsky HJ, Searle P. Interpreting nonlinear regression results. In: Graph Pad Prism Version 2.0 User’s Manual. San Diego, CA: Graph Pad Software, Inc., 1994:267–283.
Usefulness of Handgrip to Improve Ibutilide Efficacy in Organizing Atrial Electrical Activity During Atrial Fibrillation Maria Vittoria Pitzalis, MD, PhD, Massimo Grimaldi, MD, Matteo Anaclerio, MD, Massimo Iacoviello, MD, Giovanni Luzzi, MD, Cinzia Forleo, MD, and Paolo Rizzon, herapeutic strategies aimed at terminating arrhythmias are successful when they modify the mechT anisms responsible for the maintenance of the arrhythmia. The persistence of atrial fibrillation (AF) seems to depend on a critical number of wavelets depending on the size of the atrium and circuit.1,2 The wavelength is the fundamental parameter determining the size of the circuit, and depends on conduction velocity and the refractory period: when one of these variables increases, the size of the circuit increases, thus leading to a reduction in the number of circuits and favoring termination of AF. The prolongation of the refractory period, such as that obtained by class 3 antiarrhythmic drugs, has a success rate in restoring sinus rhythm of 20% to 50%.3–5 The simultaneous increase in conduction velocity could increase this percentage. Although no drugs are currently available for this purpose, it is possible that the increased adrenergic activity induced by isometric exercise6 enhances conduction velocity,7,8 leading to an organization of atrial activity. The present study sought to analyze the effect of isometric exercise (alone and in association with ibutilide infusion) on atrial electrical activity during AF. •••
Fifteen consecutive patients with persistent AF requiring internal electrical conversion to sinus rhythm gave their informed consent to participate in the study, which was approved by our local ethics committee. All patients were receiving optimal anticoagulant therapy at the time of the study and any antiarrhythmic drug previously taken had been discontinued for at From the Institute of Cardiology, University of Bari, Bari, Italy. Dr. Pitzalis’ address is: Institute of Cardiology–University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail: mariavittoria. [email protected]. Manuscript received August 14, 2000; revised manuscript received and accepted September 25, 2000.
798
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 March 15, 2001
MD
TABLE 1 Clinical Characteristics of Study Patients Age (yrs) Men/women Weight (kg) Height (cm) Left ventricular ejection fraction (%) Left atrial diameter (mm) Left atrial diameter during handgrip (mm) Underlying heart disease (no.) Systemic hypertension Valvular disease Coronary heart disease Hypertrophic cardiomyopathy Idiopathic dilated cardiomyopathy Concomitant medication (no.) Digoxin -blockers ACE inhibitors Calcium antagonists Diuretics
63 ⫾ 11 11/4 78 ⫾ 13 168 ⫾ 8 57 ⫾ 8 41 ⫾ 4 40 ⫾ 5 12 6 3 1 1 1 12 4 0 4 5 3
Values are expressed as mean ⫾ SD or number of patients. ACE ⫽ angiotensin-converting enzyme.
least 5 half-lives; none had an external cardioversion failure. In the morning, in a fasting state, all patients had 1 bipolar catheter placed in the right ventricular apex (for ventricular sensing and pacing), and 2 multipolar temporary EP-defibrillation catheters positioned in the high right atrium (VascoStim TC 2 ⫹1 CK, InControl, Weil am Rhein, Germany) and in the distal coronary sinus (VascoStim TC 3 ⫹1 DT, InControl) to record right and left atrial electrical activity. The study protocol consisted of 4 evaluations: under baseline conditions (10 minutes), after saline infusion (20 ml in 10 minutes), a first ibutilide infusion (0.87 mg or 0.01 mg/kg diluted with saline to 20 ml in 10 minutes if the patient weighed ⬍60 kg) started 10 minutes after the end of the saline infusion, 0002-9149/01/$–see front matter PII S0002-9149(00)01510-1
TABLE 2 Effects of Handgrip on Electrophysiologic and Hemodynamic Parameters Recorded Two Minutes After Saline and Ibutilide Infusions and During Handgrip Variable RA (ms) CS (ms) Heart rate (beats/min) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
Saline (n ⫽ 15) 141 139 94 131 85
⫾ ⫾ ⫾ ⫾ ⫾
29 29 18 18 7
Handgrip (n ⫽ 15) 171 165 112 157 106
⫾ ⫾ ⫾ ⫾ ⫾
24* 29† 22* 26* 10*
Ibutilide 1 (n ⫽ 13) 197 188 97 132 86
⫾ ⫾ ⫾ ⫾ ⫾
43 34 14 15 6
Handgrip (n ⫽ 13) 221 211 116 159 108
⫾ ⫾ ⫾ ⫾ ⫾
39928 40‡ 19* 24† 7*
Ibutilide 2 (n ⫽ 10) 226 215 90 132 85
⫾ ⫾ ⫾ ⫾ ⫾
48 56 14 16 7
Handgrip (n ⫽ 9) 257 246 113 155 109
⫾ ⫾ ⫾ ⫾ ⫾
69‡ 67§ 18† 22‡ 7‡
*p ⬍0.001 versus preceding phase; †p ⬍0.002 versus preceding phase; ‡p ⬍0.005 versus preceding phase; §p ⬍0.01 versus preceding phase. CS ⫽ mean atrial cycle length recorded at the level of distal coronary sinus; RA ⫽ mean atrial cycle length recorded at the level of high right atrium.
FIGURE 1. Surface electrograms recorded in lead DII, right atrial activity recorded in the high right atrium (HRA), and left atrial activity recorded in the distal coronary sinus (DCS) are shown. A, electrical activity recorded after saline infusion; B, activity recorded during handgrip, which caused organization of atrial electrical activity.
and a second ibutilide infusion started 10 minutes after the end of the first. Five minutes after the end of each of these evaluations, a handgrip test was performed using a standard device (Martin Vigormeter, Germany) on the dominant hand at 100% maximum voluntary grip strength for 15 seconds; this test was aided by a visual feedback of the force output. Electrograms were recorded throughout all phases by means of a polygraph (Bard Lab System, Lowell, Massachusetts),
and those recorded 2 minutes after each infusion and during the maximum handgrip were analyzed. Mean atrial cycle length was calculated for each phase by measuring manually all atrial cycles recorded over 10 seconds (from the fifth to the 15 second in the case of handgrip); during the same periods, mean ventricular rate was calculated. Arterial blood pressure was measured by sphygmanometer during each evaluation. In case any of the interventions led to sinus rhythm BRIEF REPORTS
799
FIGURE 2. Surface electrograms recorded in lead DII, right atrial activity recorded in the high right atrium (HRA), and left atrial activity recorded in the distal coronary sinus (DCS) are shown. A, electrical activity recorded after the second ibutilide infusion; B, activity recorded during handgrip, which caused further organization of atrial electrical activity and restoration of sinus rhythm.
restoration, the protocol was stopped; otherwise patients underwent electrical cardioversion. Before the procedure, 2-dimensional and M-mode echocardiographic measurements of the left atrial diameter during either baseline and maximum handgrip for 15 seconds were obtained (Hewlett-Packard, model 77765A, Palo Alto, California) in all patients in the left lateral recumbent position using the standard parasternal, long-axis view.9 The recordings were analyzed off-line by 2 blinded observers and measurements were averaged over at least 5 cardiac cycles. Data were analyzed using Statistica 5.0 for Windows 95 (StatSoft Inc., Tulsa, Oklahoma), and results compared using Wilcoxon’s test. A p value ⬍0.05 was considered statistically significant. Clinical characteristics of the patients are listed in Table 1. AF lasted for a median period of 66 days (range 22 to 270). The handgrip performed before the procedure, during echocardiographic evaluation, did not cause any significant modification in the left atrial diameter (Table 1), and was not associated with sinus rhythm restoration. The electrophysiologic and hemodynamic characteristics observed during the different 800 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 87
phases of the study are listed in Table 2. When all patients were considered as a whole, the value of mean atrial cycle length recorded in the right atrium did not differ from that found in the left atrium. There was no statistically significant difference between the values recorded at baseline and those recorded during saline infusion. The first ibutilide infusion led to an increase in the mean atrial cycle length compared with saline: ⫹39.7% in the right atrium (p ⬍0.001) and ⫹35.3% in the left atrium (p ⬍0.001), with evident organization of left and right atrial electrical activity. The second ibutilide infusion was associated with a further increase in mean atrial cycle length: ⫹14.7% in the right atrium (p ⬍0.005) and ⫹14.4% in the left atrium (p ⬍0.005). In all patients, maximum effort significantly increased systolic blood pressure, mean ventricular rate, and mean atrial cycle length (Table 2). Prolongation of atrial cycle length was immediately evident at the beginning of handgrip and was observed in all patients in both the right and left atria compared with each preceding condition (i.e., baseline, ⫹29.3% in the right atrium and ⫹21% in the left atrium; saline infusion, ⫹21.3% in the right atrium MARCH 15, 2001
and ⫹18.7% in the left atrium [Figure 1]; first ibutilide infusion, ⫹12.2% in the right and left atria; and second ibutilide infusion, ⫹13.7% in the right atrium and ⫹14.4% in the left atrium [Figure 2]). Sinus rhythm was restored in 10 of the 15 patients (66.7%) during the procedure: 2 after the first ibutilide infusion, 4 after the second, and 4 during the 15 seconds of maximal handgrip (1 at the 11th second of maximum handgrip after the first ibutilide infusion, and 3 at the third, ninth, and 15th second after the second ibutilide infusion). •••
The main finding of this study is that handgrip organizes atrial electrical activity during AF, thus improving our understanding of how to modify the electrophysiologic substrate of this arrhythmia and offering a new method for enhancing the cardioversion rate. Handgrip evokes an increase in sympathetic activity which, on the basis of our results, interacts with the mechanisms responsible for the maintenance of AF. According to the model suggested by Moe et al1 and Alessie,2 circuit size is of fundamental importance in favoring the maintenance of the arrhythmia; prolonging the atrial refractory period and enhancing conduction velocity are thought to favor restoration of sinus rhythm. Class III antiarrhythmic drugs are efficacious because they prolong refractoriness, an effect that was confirmed in this study by the fact that ibutilide significantly increased the mean atrial cycle length and thus led to the organization of atrial activity. However, ibutilide affects only one of the parameters considered to be critical in maintaining the arrhythmia. The only known way of enhancing conduction velocity is to increase adrenergic activity through an increase in the cyclic adenosine monophosphate levels.7,8 Handgrip is a safe and noninvasive method of increasing adrenergic activity,6 and causes a significant increase in mean atrial cycle length. This effect was clear whether the exercise was performed after saline or ibutilide infusion, but the fact that it was greatest when associated with ibutilide suggests that the 2 interventions
act differently in organizing atrial activity (1 on the refractory period, the other on conduction velocity) and thus have an additive effect. The efficacy of handgrip may also be due to its ability to reduce atrial dimension by increasing either atrial contractility10 or intrathoracic pressure, and thus reducing venous return.1,2 However, in our series, handgrip did not change left atrial diameter; therefore, the organization of AF caused by handgrip is mainly the result of enhancement in conduction velocity. In conclusion, this study shows that handgrip (alone and associated with ibutilide) can favorably modify the electrophysiologic properties of the atria during AF. These results shed new light on the possibility of enhancing the AF conversion rate by combining drugs and maneuvers that selectively act on the pathophysiologic mechanisms of AF. 1. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964;67:200 –220. 2. Alessie MA. Reentrant mechanisms underlying atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Toronto, Canada: WB Saunders, 1995:562–566. 3. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation. Circulation 1997;96:4298 – 4306. 4. Volgman AS, Carberry PA, Stambler B, Lewis WR, Dunn GH, Perry KT, Vanderlugt JT, Kowey PR. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol 1998;31:1414 –1419. 5. Vos MA, Golitsyn SR, Stangl K, Ruda MY, Van Wijk LV, Harry JD, Perry KT, Touboul P, Steinbeck G, Wellens HJ. Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998;79:568 –575. 6. Martin CE, Shaver JA, Leon DF, Thompson ME, Reddy PS, Leonard JJ. Autonomic mechanisms in hemodynamic responses to isometric exercise. J Clin Invest 1974;54:104 –115. 7. Burt JM, Spray DC. Inotropic agents modulate gap junctional conductance between cardiac myocytes. Am J Physiol 1988;254:H1206 –H1210. 8. van Rijen HVM, van Veen TAB, Hermans MMP, Jongsma HJ. Human connexin40 gap junction channels are modulated by cAMP. Cardiovasc Res 2000;45:941–951. 9. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 10. Schafers RF, Adler S, Daul A, Zeitler G, Vogelsang M, Zerkowski HR, Brodde OE. Positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in the human heart: effects of long-term beta 1-adrenoceptor antagonist treatment. J Am Coll Cardiol 1994;23:1224 –33.
BRIEF REPORTS
801