CLINICAL STUDY
Increased dispersion and shortened refractoriness caused by verapamil in chronic atrial fibrillation
Hemanth Ramanna, MDa,
Arif Elvan, MDa,
Fred H. M. Wittkampf, PhDa,
Jacques M. T. de Bakker, PhD ,
Richard N. W. Hauer, MDa and
Etienne O. Robles de Medina, MD, FACCa
a Heart-Lung Institute, University Medical Center, Utrecht, Netherlands
Interuniversity Cardiology Institute of The Netherlands, Utrecht, Netherlands. ?1
Manuscript received May 4, 2000;
revised manuscript received November 22, 2000,
accepted December 21, 2000.
Reprint requests and correspondence: Dr. Hemanth Ramanna, Heart-Lung Institute, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
 |
Abstract
|
|---|
OBJECTIVES
The objective was to assess the effect of verapamil on atrial fibrillation (AF) cycle length and spatial dispersion of refractoriness in patients with chronic AF.
BACKGROUND
Previous studies have suggested that verapamil prevents acute remodeling by AF. The effects of verapamil in chronic AF are unknown.
METHODS
During electrophysiologic study in 15 patients with chronic AF (duration >1 year), 12 unipolar electrograms were recorded from right atrial free wall, right atrial appendage and coronary sinus, along with monophasic action potential recordings from the right atrial appendage. The mean fibrillatory interval at each atrial recording site was used as an index for local refractoriness. Dispersion of refractoriness was calculated as the standard deviation of all local mean fibrillatory intervals expressed as a percentage of the overall mean fibrillatory interval. After baseline measurements, verapamil (0.075 mg/kg intravenous in 10 min) was infused and the measurements were repeated.
RESULTS
After administration of verapamil, mean fibrillatory intervals shortened by a mean of 16.6 ± 3.3 ms (p < 0.001) at the right free wall, 15.0 ± 3.5 ms (p < 0.001) at the appendage and 17.1 ± 3.2 ms (p < 0.01) in the coronary sinus. Monophasic action potential duration decreased by 15.9 ± 4.0 ms (p < 0.01). Dispersion of refractoriness increased in all patients from 3.8 ± 0.8 to 5.1 ± 1.8 (p < 0.001). A strong correlation between mean fibrillatory intervals and action potential duration was found, both before and after verapamil.
CONCLUSIONS
Verapamil caused shortening of refractoriness and increase in spatial dispersion of refractoriness in patients with chronic AF. This implies that verapamil is not useful in reversing the remodeling process in these patients.
|
Abbreviations and Acronyms
| | AF | = atrial fibrillation | | APD90 | = monophasic action potential duration | | CS | = coronary sinus |
|
Experimental and human studies have shown that atrial fibrillation (AF) causes remodeling (1–8), that is, shortening of the refractory period and increase in spatial dispersion of refractoriness. Clinical and experimental studies have shown that the longer AF is allowed to exist, or remodeling is allowed to continue, the more difficult it becomes to obtain sinus rhythm (9). Intracellular calcium overload has been suggested as the mechanism for remodeling. Recent reports have suggested that calcium entry blockers such as verapamil prevent remodeling (8,10,11). However, all of these studies were carried out in models of recent-onset AF. In addition, despite extensive clinical experience with verapamil, antifibrillatory effects of verapamil have not become apparent. On the contrary, an earlier study by Shenasa et al. (12) showed that AF episode duration increased after verapamil administration. In addition, a recent experimental study by Lee et al. (13) showed that verapamil was useless in preventing remodeling in AF of longer duration. These authors also showed that verapamil increases atrial vulnerability and the duration of induced AF episodes. The present study was performed to assess the effect of verapamil on atrial fibrillation cycle length and spatial dispersion of refractoriness in patients with chronic AF.
|
Methods
|
|---|
Patients.
We studied 15 consecutive patients (average age 64.8 ± 14.2 years, eight females) with chronic AF (duration of permanent AF >1 year). The underlying etiologies for AF were idiopathic (three patients), mitral valve disease (five patients), postinfarct (three patients), idiopathic dilated cardiomyopathy (two patients) and hypertension (two patients). The reason for electrophysiologic study was His bundle ablation for drug-refractory AF in 14 patients and diagnosis in one patient. All antiarrhythmic drugs had been discontinued for at least five half-lives and no patient was on amiodarone. All patients gave informed consent and the study was approved by the hospital ethical review board.
Study protocol.
Electrophysiologic study was performed in the fasting nonsedated state. Femoral venous access was obtained using local anesthesia. In all patients, a decapolar electrode catheter (interelectrode spacing 5 mm) was positioned against the right lateral free wall as described previously (14). In the first eight patients, a quadripolar catheter was positioned in the right atrial appendage. In these patients, arterial pressure and right atrial pressure were continuously measured. In the final seven patients, the quadripolar catheter was positioned in the coronary sinus (CS) and a quadripolar Franz catheter (EPT, Sunnyvale, California) was used to record monophasic action potentials from the right atrial appendage. Twelve unipolar electrograms (filter 0.05 to 500 Hz) were recorded from the decapolar catheter and the two proximal electrodes from the quadripolar catheters (14). The catheters were positioned to obtain a minimum of eight electrogram recordings with amplitude >0.5 mV. The atrial electrograms, surface leads (I, II, III, V1), pressure tracings and monophasic action potentials were recorded using an electrophysiological system (Cardiolab, Prucka Engineering, Houston, Texas).
A 3-min period of AF was acquired. Verapamil (0.075 mg/kg) was then administered intravenously in 10 min. One minute after completion of verapamil infusion, another 3 min of fibrillatory electrograms were acquired.
Data analysis.
The technique used to measure fibrillatory intervals and to calculate spatial dispersion of refractoriness has been described previously (14). Fibrillatory intervals were measured by detecting the intrinsic negative deflections. For each atrial recording site, histograms of fibrillatory intervals were plotted. Undersensing of intrinsic deflections was detected by observation of secondary peaks in the histogram. Such intervals were discarded (15). The mean fibrillatory interval at each recording site was used as an index for local refractoriness (16). Dispersion of refractoriness was measured by calculating the coefficient of dispersion. This was defined as the standard deviation of the mean of all mean local fibrillatory intervals expressed as a percentage of the overall mean fibrillatory interval (14). Electrograms from the Franz catheter were used to measure monophasic action potential durations (APD90) before and after verapamil administration (17).
Statistical analysis.
At each individual recording site, fibrillatory intervals and APD90 before and after verapamil were compared using Student t test. Pre- and postverapamil mean fibrillatory intervals, mean APD90, arterial and right atrial pressures for the total patient group were compared using a paired t test. Correlation coefficients between local fibrillatory interval and APD90 were calculated both before and after verapamil. A p value of  0.05 was considered statistically significant.
|
Results
|
|---|
In each patient, mean fibrillatory intervals significantly shortened at all individual atrial recording sites after verapamil (Fig. 1, Table 1). The average drop in AF cycle length was 16.6 ± 3.3 ms (p < 0.001) at the right free wall, 15.0 ± 3.5 ms (p < 0.001) at the appendage and 17.1 ± 3.2 ms (p < 0.001) in the CS. The shortening of fibrillatory intervals is further demonstrated in Figure 2, which shows histograms at a single recording site before and after verapamil. The histogram shape remains unchanged despite the shortening of fibrillatory intervals. Data per individual patient are shown in Table 2. Decrease in mean fibrillatory intervals per recording site and a decrease in monophasic action potential duration in the right atrial appendage were highly significant. As shown in Figure 3, there was a strong correlation between APD90 and local mean fibrillatory interval both before and after verapamil administration (r = 0.989; p < 0.001 and r = 0.990; p < 0.001, respectively). The relationship between APD90 and local mean fibrillatory interval remained unchanged by verapamil. Dispersion of mean fibrillatory intervals in the right atrium increased significantly as shown in Table 1. No significant differences were found between free wall, appendage and CS. Arterial pressure and right atrial pressure did not change significantly in any patient.
View larger version (45K):
[in this window]
[in a new window]
|
Figure 1 Electrogram recordings before (left) and after (right) verapamil administration. The electrograms from the decapolar catheter at the right atrial free wall are designated E1 to E10; those from the coronary sinus CS1 to CS4 and the monophasic action potential recording MAP. The mean fibrillatory interval shortened at each recording site. The signal quality in E1 was inadequate for measurement of fibrillatory intervals. This recording site was excluded from the analysis.
|
|
View larger version (15K):
[in this window]
[in a new window]
|
Figure 2 Histograms of fibrillatory intervals before and after verapamil administration at a single atrial recording site. The administration of verapamil caused shortening of fibrillatory intervals without changing the distribution of these fibrillatory intervals. Black bar = control; white bar = verapamil.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 3 Mean fibrillatory interval and action potential duration (APD90) were measured in the right atrial appendage in seven patients. For each of these patients, mean fibrillatory interval (x-axis) and APD90 (y-axis) are plotted both before (black boxes) and after (white boxes) verapamil. Both mean fibrillatory intervals as well as APD90 shortened significantly in each patient. The relationship between mean fibrillatory interval and APD90 is linear both before and after verapamil administration, and the relationship between both parameters remains unchanged.
|
|
|
Discussion
|
|---|
To our knowledge, this is the first study in patients with chronic AF to assess the acute effects of verapamil on AF cycle length and spatial dispersion of refractoriness. Verapamil caused a decrease in mean fibrillatory intervals and an increase in spatial dispersion. This study suggests that verapamil does not reverse remodeling in chronic atrial fibrillation. Finally, verapamil did not alter the linear relationship between AF cycle length and APD90, suggesting that verapamil does not alter the excitable gap during AF.
Verapamil in atrial fibrillation.
Atrial fibrillation is believed to produce electrophysiologic changes in the atrial myocardium, known as remodeling, which in turn facilitate the perpetuation of AF (1–8). This phenomenon has been attributed to intracellular calcium overload (8,10,11,18). Recent studies have suggested that verapamil prevents remodeling caused by pacing-induced AF (8,10,11). All of these studies were performed in models of recent-onset AF. However, antifibrillatory effects of verapamil have not been demonstrated in a clinical setting.
In an earlier study Shenasa et al. (12) administered verapamil both intravenously and orally in a maintenance dose to patients for treatment of supraventricular tachycardia. The duration of electrically induced AF episodes significantly increased after both intravenous and oral verapamil administration. At the time of that study, this finding remained unexplained. In a recent study, Lee et al. (13) demonstrated that verapamil was unable to prevent remodeling after one and six weeks of pacing-induced AF in a canine model. In addition, verapamil increased the duration of induced AF episodes. Lee et al. (13) also showed that atrial conduction velocity remained unchanged by verapamil administration. The present study showed that verapamil caused shortening of atrial refractoriness in patients. Therefore, the wavelength of reentrant wavelets, being the product of conduction velocity and refractoriness, would also become shorter (1). This would in turn promote AF perpetuation. This conclusion is supported by several studies that have demonstrated increased AF duration caused by shortened refractoriness (1,5–8,10). Thus, the verapamil-induced shortening of atrial refractoriness as found in our study may be the underlying mechanism of the increased AF duration.
Several studies reported increased atrial vulnerability after verapamil administration (19). In a previous study by our group in patients without structural heart disease (14), dispersion of refractoriness was measured using the same catheter-based technique described in the present study. Atrial vulnerability was assessed using a staged stimulation protocol starting with single extrastimuli followed by more aggressive pacing to induce AF. Increased dispersion of refractoriness was strongly associated with increased atrial vulnerability. An increase in dispersion of refractoriness as found in the present study after verapamil administration may explain the increased atrial vulnerability found in experimental studies.
Methodological considerations.
Mean fibrillatory intervals were used as an index for local refractory periods. This method, validated in previous studies (16,17,20,21), is the only practical technique to simultaneously evaluate changes of refractoriness at multiple sites in patients with chronic AF. Every patient provided his or her own control data for comparison with data obtained after verapamil administration.
Some drugs such as procainamide, flecainide and ibutilide are known to alter the excitable gap during AF. After administration of such drugs, AF cycle length no longer correlates with APD90 and local refractoriness (1,17). In our patients, however, a strong correlation was observed between AF cycle length and APD90 both before and after verapamil administration, as shown in Figure 3. Therefore the verapamil-induced decrease in fibrillatory cycle length would be more likely to be caused by a decrease in refractory period rather than a change in excitable gap.
Autonomic blockade was not used in the present study because beta-blockade in combination with verapamil was considered potentially hazardous for the studied patients. Verapamil effects may be mediated through a sympathetic response caused by verapamil-induced hypotension, as suggested by Friedman et al. (21). These investigators administered a bolus of verapamil 0.2 mg/kg in an anesthetized canine preparation. This resulted in a decrease of arterial pressure and an increase in right atrial pressure, followed by enhanced sympathetic activity. These authors suggested that this increased sympathetic activity was solely responsible for the increased duration of AF episodes and the increased atrial vulnerability. In our patients, however, the verapamil dose was much lower (0.075 mg/kg) and was injected slowly in 10 min. Absence of significant changes in arterial or right atrial pressures suggested that intense sympathetic activity did not occur. In addition, Lee et al. (13) reported increased AF duration after verapamil during autonomic blockade with propranolol and atropine. These findings suggest that the mechanism of the increased duration of AF episodes in our study is not mediated by sympathetic reflex activity.
Mechanistic implications.
Several studies have provided evidence that intracellular calcium overload is the underlying mechanism of electrophysiologic remodeling (8,10,11,18). During rapid pacing, L-type calcium channel blockade prevents calcium influx and thus acute remodeling (10). However, remodeling is associated not only with calcium influx but also with changes in gap junction distribution (3) and structural cellular (4,6,18) and metabolic changes at a later stage. These changes may contribute to a different response to verapamil at later stages of AF.
Conclusions.
Although verapamil is effective for ventricular rate control, our data suggest that it is not useful for reversing or preventing further remodeling in patients with chronic AF. Verapamil did not alter the relationship between AF cycle length and APD90, suggesting that the excitable gap during AF was not affected by verapamil.
|
Footnotes
|
|---|
This study was partially supported by a grant from the Interuniversity Cardiology Institute of The Netherlands.
|
References
|
|---|
1. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968[Abstract/Free Full Text]
2. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation. 1996;94:2953–2960[Abstract/Free Full Text]
3. Elvan A, Huang XD, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation. 1997;96:1675–1685[Abstract/Free Full Text]
4. Ausma J, Wijffels MC, van Eys G, et al. Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation. Am J Pathol. 1997;151:985–997[Abstract]
5. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–525[Abstract/Free Full Text]
6. Gaspo R, Bosch RF, Talajic M, Nattel S. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation. 1997;96:4027–4035[Abstract/Free Full Text]
7. Fareh S, Villemare C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation. 1998;98:2202–2209[Abstract/Free Full Text]
8. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation. 1997;96:1542–1550[Abstract/Free Full Text]
9. Crijns HJGM, Van Gelder IC, Van Gilst WH, Hillege H, Gosselink K, Lie KI. Serial antiarrhythmic drug therapy to maintain sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter. Am J Cardiol. 1991;68:335–341[CrossRef][Medline]
10. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation. 1996;94:2968–2974[Abstract/Free Full Text]
11. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation. 1997;95:1945–1953[Abstract/Free Full Text]
12. Shenasa M, Kus T, Fromer M, LeBlanc RA, Dubuc M, Nadeau R. Effects of intravenous and oral calcium antagonists (diltiazem and verapamil) on sustenance of atrial fibrillation. Am J Cardiol. 1988;62:403–407[CrossRef][Medline]
13. Lee SH, Yu WC, Cheng JJ, et al. Effect of verapamil on long-term tachycardia-induced atrial electrical remodeling. Circulation. 2000;101:200–206[Abstract/Free Full Text]
14. Ramanna H, Hauer RNW, Wittkampf FHM, et al. Identification of the substrate of atrial vulnerability in patients with idiopathic atrial fibrillation. Circulation. 2000;101:995–1001[Abstract/Free Full Text]
15. Opthof T, Ramdat Misier A, Coronel R, et al. Dispersion of refractoriness in canine ventricular myocardium. Effects of sympathetic stimulation. Circ Res. 1991;68:1204–1215[Abstract/Free Full Text]
16. Lammers WEJP, Schalij MJ, Kirchoff CJHJ, Allessie MA. Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol. 1990;28:H1254–H1263
17. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibitilide compared with procainamide during human atrial fibrillation. Circulation. 1997;96:4298–4306[Abstract/Free Full Text]
18. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing: structural, functional and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595[Abstract/Free Full Text]
19. Capucci A, Biffi M, Boriani G, et al. Dynamic electrophysiological behavior of human atria during paroxysmal atrial fibrillation. Circulation. 1995;92:1193–1202[Abstract/Free Full Text]
20. Kim KB, Rodefeld MD, Schuessler RB, Cox JL, Boineau JP. Relationship between local atrial fibrillation interval and refractory period in the isolated canine atrium. Circulation. 1996;94:2961–2967[Abstract/Free Full Text]
21. Friedman HS, Rodney E, Sinha B, et al. Verapamil prolongs atrial fibrillation by evoking an intense sympathetic neurohumoral effect. J Invest Med. 1999;47:293–303[Medline]
This article has been cited by other articles:
|
|
|
|
 
Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society
Europace,
September 1, 2006;
8(9):
651 - 745.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al.
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society
J. Am. Coll. Cardiol.,
August 15, 2006;
48(4):
e149 - e246.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al.
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society
Circulation,
August 15, 2006;
114(7):
e257 - e354.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kumagai, H. Nakashima, H. Urata, N. Gondo, K. Arakawa, and K. Saku
Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation
J. Am. Coll. Cardiol.,
June 18, 2003;
41(12):
2197 - 2204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Hassan, H. Oral, C. Scharf, A. Chugh, F. Pelosi, B. P. Knight, S. A. Strickberger, and F. Morady
Rate-dependent effect of verapamil on atrial refractoriness
J. Am. Coll. Cardiol.,
February 5, 2003;
41(3):
446 - 451.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Sticherling, H. Tada, W. Hsu, A. C. Bares, H. Oral, F. Pelosi, B. P. Knight, S. A. Strickberger, and F. Morady
Effects of Diltiazem and Esmolol on Cycle Length and Spontaneous Conversion of Atrial Fibrillation
Journal of Cardiovascular Pharmacology and Therapeutics,
June 1, 2002;
7(2):
81 - 88.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Shimizu and O. A. Centurion
Electrophysiological properties of the human atrium in atrial fibrillation
Cardiovasc Res,
May 1, 2002;
54(2):
302 - 314.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Goette, G. Juenemann, B. Peters, H. U. Klein, A. Roessner, C. Huth, and C. Rocken
Determinants and consequences of atrial fibrosis in patients undergoing open heart surgery
Cardiovasc Res,
May 1, 2002;
54(2):
390 - 396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kurita, H. Mitamura, A. Shiroshita-Takeshita, A. Yamane, M. Ieda, O. Kinebuchi, T. Sato, S. Miyoshi, M. Hara, S. Takatsuki, et al.
Daily oral verapamil before but not after rapid atrial excitation prevents electrical remodeling
Cardiovasc Res,
May 1, 2002;
54(2):
447 - 455.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods