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Circulation. 1996;93:1747-1754

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(Circulation. 1996;93:1747-1754.)
© 1996 American Heart Association, Inc.

Articles

Atrial Contractile Dysfunction After Short-term Atrial Fibrillation Is Reduced by Verapamil but Increased by BAY K8644

Elisabeth Leistad, MD, PhD; Gunnar Aksnes, MD, PhD; Esther Verburg, BSc; Geir Christensen, MD, PhD

From the Institute for Experimental Medical Research (E.L., G.A., E.V., G.C.) and Research Forum (E.L., E.V., G.C.), University of Oslo, Ullevål Hospital, Oslo, Norway.

Correspondence to Elisabeth Leistad, MD, PhD, Institute for Experimental Medical Research, University of Oslo, Ullevål Hospital, N-0407 Oslo 4, Norway. E-mail elisabeth.leistad@ioks.uio.no.


*    Abstract
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 *Abstract
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 down arrowResults
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Background Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation. Accordingly, we examined the effects of drugs that reduce or increase transsarcolemmal calcium influx on postfibrillation atrial dysfunction. Furthermore, we examined whether the dysfunction could be attributed to atrial ischemia.

Methods and Results Atrial contractility after atrial fibrillation was examined in open-chest pigs paced with a constant ventricular rate after complete AV block. Atrial contractility was computed as systolic shortening of left atrial diameter divided by atrial preload. Three groups of six pigs each were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. Verapamil or the calcium channel agonist BAY K8644 was administered intravenously before the second fibrillation period. The degree and duration of postfibrillation atrial contractile dysfunction were reduced with verapamil but increased with BAY K8644. In a control group, parallel changes occurred after the first and second fibrillation periods. Atrial tissue content of creatine phosphate declined slightly during fibrillation, whereas the tissue content of ATP and lactate remained unchanged.

Conclusions Atrial contractile dysfunction after short-term atrial fibrillation is reduced by the calcium antagonist verapamil, which suggests that transsarcolemmal calcium influx contributed to this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial contractile dysfunction. Atrial ischemia was not observed during fibrillation.


Key Words: fibrillation • calcium channels • drugs • contractility • atrium


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Atrial fibrillation is a common arrhythmia associated with an increased risk of cardiovascular morbidity1 and mortality.2 Rapid, asynchronous atrial contractions during fibrillation result in a loss of atrial booster-pump function, which results in a decline in ventricular filling and cardiac output. The loss of a synchronized atrial contraction also leads to reduced atrial blood flow velocity, which favors the development of atrial thrombi.3 4 Accordingly, atrial fibrillation is the most frequent cause of cerebral embolism, accounting for 15% of all strokes.5 Conversion to sinus rhythm is therefore frequently attempted to improve cardiac performance and reduce the incidence of thrombus formation.

After conversion of atrial fibrillation, atrial contractility may be reduced or even absent for up to several weeks despite normal electric activity recorded by electrocardiogram.6 7 8 After cardioversion, the development of or an increase in left atrial and left atrial appendage spontaneous echocontrast, which is a swirling pattern of echo densities, is often observed.9 10 11 Spontaneous echocontrast has been shown to be strongly associated with left atrial appendage thrombus formation and embolic events10 11 12 and is related to reduced blood flow velocity with low shear rates and erythrocyte aggregation.13 Traditionally, it has been assumed that embolism in connection with cardioversion results from dislodgment of preexisting atrial thrombi after prompt return of atrial contraction. However, recent studies9 10 11 suggested that reduced contractility of the atrium or atrial appendage reduces atrial blood flow and also favors the development of atrial thrombi after cardioversion. Accordingly, improvement of atrial contractility after cessation of atrial fibrillation might reduce the risk of thrombus formation after cardioversion.

Factors that might contribute to reduced atrial contractility after cessation of atrial fibrillation, also termed atrial stunning, have been discussed.6 11 14 15 However, the mechanism is unknown, and no treatment has been suggested. Anesthesia and electric energy delivered during cardioversion may impair cardiac function, but reduced atrial contractility is also seen after pharmacological conversion.16 A primary atrial myocardial disease14 as well as a chronic rheumatic disease of the atrial myocardium15 have also been suggested to account for the delayed return of atrial contractility.

Reduced atrial contractility has been observed after short-term or paroxysmal atrial fibrillation.17 18 In a previous study,18 we demonstrated changes in atrial contractility after the cessation of periods of atrial fibrillation of 1 to 30 minutes in duration. The magnitude and duration of the reduced atrial contractility depended on the duration of the preceding atrial fibrillation. Surprisingly, we found that atrial contractility was increased in the first seconds after atrial fibrillation before a longer period of reduced atrial contractility ensued. On the basis of these observations, we hypothesized that cytosolic calcium overload due to the rapid depolarizations during the preceding fibrillation might be responsible for the atrial contractile dysfunction. This hypothesis had been suggested but not evaluated by Shapiro et al6 in 1988. It has been shown that cytosolic calcium increases with a high depolarization rate during regular pacing19 20 and that transient calcium overload may induce contractile dysfunction.21 22 Another suggested explanation for the contractile dysfunction is that the fibrillating atrial myocardium is ischemic because of high energy demand.6 After ischemia, both an initial hypercontractility and an ensuing hypocontractility have been observed.23

The first aim of the present study was to examine whether atrial contractile dysfunction after atrial fibrillation is influenced by drugs that alter the calcium influx via the sarcolemmal L-type calcium channels. Experiments were performed in open-chest, anesthetized pigs, and atrial fibrillation was induced by continuous rapid atrial pacing. By performing separate atrial and ventricular pacing after complete AV block,24 we were able to avoid the confounding effect of ventricular arrhythmia. We examined the effect of the calcium channel antagonist verapamil on postfibrillation atrial dysfunction. This drug is frequently used in the treatment of patients with acute and chronic atrial fibrillation. In addition, verapamil was considered particularly suitable for the purpose of reducing calcium influx during atrial fibrillation because its calcium antagonism increases with increasing frequency of depolarization.25 26 In a separate group of animals, we examined the effect of the calcium channel agonist BAY K8644 on postfibrillation dysfunction. BAY K8644 increases calcium influx through the L-type calcium channels.

The second aim of the present study was to determine whether atrial contractile dysfunction after cessation of fibrillation could be attributed to ischemia during atrial fibrillation. Thus, ATP, CrP, and lactate were measured in freeze-clamped biopsy samples from the atria before, during, and after atrial fibrillation in a separate group of animals.


*    Methods
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 *Methods
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Surgical Preparation
All experiments and animals were handled in accordance with the requirements set by the Norwegian Council for Animal Research. Twenty-five pigs of either sex (weight, 18 to 29 kg) were fasted for 24 hours and anesthetized with a bolus dose of pentobarbital sodium 25 mg/kg IP, which was supplemented by 5 to 20 mg · kg-1 · h-1 IV to maintain a constant level of anesthesia. The animals were ventilated via tracheostomy with a volume-regulated respirator (model 101, Princeton Medical Instruments). Oxygen supplement, tidal volume, and ventilation frequency were adjusted to keep arterial PO2, PCO2, and pH within normal ranges. The body temperature was kept constant by use of an electric heating pad and wrappings.

The heart was exposed through a midsternal split and an incision in the left fourth intercostal space. The pericardium was opened, and the heart was suspended in a pericardial cradle. The AV node was blocked by injection of 0.5 mL formalin 36% according to the method described by Steiner and Kovalik.24 The atria were paced by electrodes sutured to the right atrial appendage with a constant frequency slightly above the spontaneous heart rate. The ventricles were paced with the same frequency from the His bundle with 120-ms AV delay. The pacing electrodes were connected to a stimulator (model 5837, Medtronic Inc) that delivered 2-ms square-wave pulses of 10 V (double threshold value). Atrial fibrillation was induced by continuous stimulation of the right atrium at 15 Hz, as described previously,18 while the ventricular rate was kept unchanged.

A femoral artery and vein were cannulated for arterial blood gas sampling and intravenous infusions, respectively. Heparin (750 IU/kg) was given to prevent blood clotting in the pigs in the verapamil, BAY K8644, and control groups.

Hemodynamic Measurements
Hemodynamic measurements were obtained from the 18 pigs randomly assigned to receive verapamil or BAY K8644 or to serve as the control group. Left atrial cross-sectional diameter was recorded by ultrasonic external-diameter transducers (Triton Technology) sutured to the atrial surface as previously described.27 Left atrial diameter was measured as the diameter between the medial and lateral walls of the left atrium. One transducer was placed near the pulmonary artery in the groove between the aorta and the left atrium and the other on the lateral surface of the atrium close to the left ventricle.

Two microtipped pressure-transducer catheters (model PC-40, Millar Instruments) were used to record pressure in the left atrium and left ventricle. Both catheters have a frequency response of 10 kHz. The catheter that was used to measure left atrial pressure was introduced through the left atrial appendage and secured by small purse-string sutures, and the catheter in the left ventricle was introduced via the right common carotid artery. Any drift in the pressure-recording system was detected by comparison with pressure recordings obtained through the fluid-filled side channels of the Millar catheters, connected to Statham P23 Gb pressure transducers (Gould Instruments). This system has a frequency response of 40 Hz. A fluid-filled catheter for arterial blood gas sampling was also introduced into the aorta via the right femoral artery and connected to a Statham P23 Gb transducer.

All hemodynamic variables were continuously monitored on an 8-channel galvanometric recorder (model 7758 B, Hewlett-Packard). On-line data acquisition and later analysis were written and performed in ASYST (Asyst Software Technologies, Inc), as described previously.18

Left atrial systolic shortening was computed as the difference between the atrial diameter at the onset of the atrial A wave and the atrial minimal diameter (Fig 1Down). Since atrial contractility depends on atrial preload, we calculated the LASSindex as LASS divided by atrial preload (the atrial diameter at onset of atrial contraction28 ). The value of LASSindex before each period of atrial fibrillation was set to 100%. Left atrial afterload was assessed from the left ventricular segment–length recordings at the onset of atrial contraction. The left ventricular segment lengths measured a part of the ventricular wall circumference and were obtained from one pair of ultrasonic transducers sewn into the midmyocardium. One ultrasonic transmitter and one ultrasonic receiver were placed 7 to 15 mm apart perpendicular to the axis of contraction parallel to the first and second branches of the left anterior descending coronary artery.



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  		Figure 1. Representative tracings from one experiment showing left atrial pressure and diameter during AV pacing. LASS is the difference between left atrial diameter at the onset of atrial contraction (atrial preload) and atrial minimal diameter.

Experimental Design
The first 18 pigs in the present study were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. The first period of atrial fibrillation was used as the control. Recordings of hemodynamic variables were obtained during AV pacing before each period of atrial fibrillation and at 5, 15, and 30 seconds as well as 1, 2, 3, 4, 5, 10, 15, and 20 minutes after cessation of fibrillation. All atrial parameters had returned to normal values before the second period of fibrillation was initiated.

In the verapamil group (n=6), verapamil (0.2 mg/kg IV) was injected 60 minutes after the first period of atrial fibrillation. The second period of atrial fibrillation was initiated when the hemodynamic recordings reached a new steady state. In the BAY-K group (n=6), BAY K8644 (2.0 µg·kg-1·min-1 IV) was infused continuously throughout the recordings before and after the second atrial fibrillation period. In the control group (n=6), no drugs were given between the first and second atrial fibrillation periods. To compare the duration of atrial hypocontractility (LASSindex below the value obtained before fibrillation) within a group, the maximal reduction in LASSindex was determined. Thereafter, the time from the onset of atrial hypocontractility to the time when 80% restitution of contractility occurred was assessed. Heart rate was maintained at a constant level in each experiment, and there was no significant difference in heart rate between the groups.

Seven separate pigs were used for metabolic measurements. Because ATP concentrations do not fall early in ischemia and it takes time before lactate production occurs, a relative ischemia would be difficult to detect after 5 minutes of fibrillation. Accordingly, biopsy samples were obtained from the atrial myocardium during a control period, after 25 minutes of atrial fibrillation, and 30 minutes after cessation of atrial fibrillation. Lactate was also determined in atrial biopsy samples obtained after 10 minutes of left atrial ischemia. Ischemia was induced by ligation of the circumflex coronary artery, which supplies the left atrium in the pig.29 The biopsy samples were obtained by freeze-clamping the atrial tissue in vivo with pinchers cooled in liquid nitrogen (-70°C) and were stored at -70°C until analysis. Before analysis, each biopsy sample was dissected into two to three specimens, avoiding parts that macroscopically contained blood and fat. ATP, CrP, and lactate were determined enzymatically in 3 mol/L perchloric acid extracts neutralized by 2 mol/L potassium hydrogen carbonate. ATP and CrP contents were determined by luminescence,30 and lactate was determined by UV spectrophotometry.31 According to our measurements, minimum detection levels of ATP and lactate with a power of 0.8 would be 0.5 and 0.75 mmol/kg wet weight, respectively.

Statistics
Values are presented as mean±SEM. The Friedman nonparametric ANOVA with an extension for multiple comparisons32 was used for repeated measurements. The Wilcoxon two-tailed signed rank test was used for paired statistical analysis when two groups of data were compared. A probability value of P<.05 was considered statistically significant.


*    Results
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 up arrowIntroduction
 up arrowMethods
 *Results
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Verapamil Group
LASS was 5.9±0.5 mm during control conditions before atrial fibrillation (LASSindex 100%; Fig 2Down). After cessation of the 5-minute atrial fibrillation period, LASS immediately increased to 6.9±0.4 mm, which corresponds to an increase in LASSindex to 119.0±6.2%. The brief phase of atrial hypercontractility (LASSindex>100%) was followed by a period of atrial hypocontractility (LASSindex<100%). During this period of hypocontractility, LASS reached a nadir of 4.7±0.6 mm (LASSindex 77.8±5.2%). LASS remained below the control level for several minutes but gradually increased and was not significantly different from control 10 minutes after cessation of atrial fibrillation.



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  		Figure 2. The effect of verapamil on atrial contractile dysfunction after atrial fibrillation. *P<.05 versus value obtained before atrial fibrillation (100%).

Left atrial preload and afterload were 30.6±1.6 and 10.2±1.1 mm, respectively, during control conditions and were not significantly different after cessation of fibrillation. Maximal left ventricular systolic pressure, its maximal positive first derivative (LV dP/dt), and mean aortic pressure were not significantly altered from the control values of 92±7 mm Hg, 1493±118 mm Hg/s, and 82±4 mm Hg, respectively.

Injection of verapamil reduced mean aortic pressure from 82±4 to 75±5 mm Hg. Maximal left ventricular systolic pressure and LV dP/dt declined from 95±5 to 89±7 mm Hg and from 1434±74 to 1184±46 mm Hg/s, respectively. However, injection of verapamil did not significantly affect LASS, atrial preload, or left ventricular segment length.

After injection of verapamil, LASS was 6.2±0.5 mm before atrial fibrillation and 6.9±0.4 mm immediately after cessation of fibrillation (P=NS). LASSindex increased immediately after fibrillation to 108.8±3.6% (P<.05) (Fig 2Up). Thereafter, a period of atrial hypocontractility ensued. However, the magnitude of the atrial hypocontractility was significantly reduced. During this period of hypocontractility, LASS reached a nadir of 5.6±0.5 mm (LASSindex 92.5±2.4%) after verapamil, compared with 4.7±0.6 mm (LASSindex 77.8±5.2%) before verapamil (P<.05). Verapamil also reduced the duration of atrial hypocontractility, and LASSindex was not significantly different from control by 2 minutes after fibrillation. Before verapamil, time to 80% restitution of atrial contractility was 6.9±0.9 minutes. After verapamil, this was significantly reduced to 2.5±0.7 minutes (P<.05). After cessation of fibrillation, left atrial preload and afterload were not significantly different from the values of 30.7±5.0 and 10.2±1.2 mm, respectively, obtained before atrial fibrillation. Similarly, mean aortic pressure, maximal left ventricular systolic pressure, and LV dP/dt were not significantly altered after fibrillation.

BAY K8644 Group
During control conditions, LASS was 5.2±0.4 mm before atrial fibrillation (LASSindex 100%; Fig 3Down). After the 5-minute atrial fibrillation period, LASS immediately increased to 5.7±0.3 mm, which corresponds to an increase in LASSindex to 108.0±3.0% 5 seconds after fibrillation. This brief hypercontractile phase was followed by a period of atrial hypocontractility. During this hypocontractile period, LASS reached a nadir of 4.1±0.6 mm (LASSindex 76.6±7.7%). LASS remained below control values in the next few minutes but gradually increased and was not significantly different from control after 10 minutes.



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  		Figure 3. The effect of BAY K8644 (Bay-K) on atrial contractile dysfunction after atrial fibrillation. *P<.05 versus value obtained before atrial fibrillation (100%).

Atrial preload and afterload were 28.7±1.2 and 9.4±04 mm, respectively, during control conditions and were not significantly different after cessation of the 5-minute atrial fibrillation period. Similarly, after fibrillation, there were no significant alterations in mean aortic pressure, maximal left ventricular systolic pressure, and LV dP/dt from the respective values of 95±4 mm Hg, 111±8 mm Hg, and 1720±221 mm Hg/s obtained before fibrillation.

When steady state was reached during infusion of BAY K8644, mean aortic pressure had increased from 96±5 to 114±6 mm Hg. Maximal left ventricular systolic pressure increased from 112±7 to 145±7 mm Hg and LV dP/dt from 1744±213 to 2213±320 mm Hg/s. LASS increased from 5.1±1.3 to 6.8±0.3 mm. Left atrial preload and left ventricular segment length, however, were not different from the values (29.0±1.2 mm and 9.5±04 mm) obtained before infusion of BAY K8644.

When atrial fibrillation was induced during infusion of BAY K8644, postfibrillation atrial dysfunction was aggravated compared with before BAY-K infusion. LASS was 6.8±0.3 mm during BAY-K infusion before atrial fibrillation. After cessation of atrial fibrillation, the increase in LASS to 7.1±0.2 mm (LASSindex 105.2±6.0%; Fig 3Up) did not reach statistical significance. However, a period of marked atrial hypocontractility ensued, and LASS declined below control levels to a nadir of 4.7±0.7 mm (P<.05). The postfibrillation nadir in LASSindex was 67.9±7.6%, which was significantly lower than the value of 76.6±7.7% obtained before infusion of BAY K8644 (P<.05). Thereafter, LASS gradually increased and was not significantly different from control after 15 minutes. Before infusion of BAY K8644, time to 80% restitution in atrial contractility after cessation of atrial fibrillation was 8.1±1.2 minutes. This was significantly increased to 15.9±3.0 minutes during infusion of BAY K8644. Thus, BAY K8644 significantly aggravated both the magnitude and duration of postfibrillation atrial dysfunction. After cessation of fibrillation, left atrial preload and afterload were not significantly different from the values of 29.6±1.6 mm and 9.4±0.4 mm obtained before atrial fibrillation. Similarly, mean aortic pressure, maximal left ventricular systolic pressure, and LV dP/dt did not change from before to after cessation of fibrillation.

Control Group
LASS was 5.8±0.6 mm before each period of atrial fibrillation. Five seconds after the first fibrillation period, LASS increased to 6.9±0.4 mm, corresponding to an increase in LASSindex to 121.0±6.3%. After the second fibrillation period, LASS increased to 6.8±0.3 mm (LASSindex 119.0±6.2%), which was not significantly different from the hypercontractility observed after the first fibrillation period. This brief phase of atrial hypercontractility was followed by a 5-minute period of atrial hypocontractility after both the first and second fibrillation periods. After the first fibrillation period, LASS reached a nadir of 4.1±0.6 mm by 15 seconds after fibrillation, corresponding to a minimum LASSindex value of 69.5±4.9%. After the second atrial fibrillation period, LASS decreased to a nadir of 4.0±0.6 mm (LASSindex 68.3±4.8%). Time to 80% restitution of atrial contractility after atrial fibrillation was not significantly different between the first and second fibrillation periods. Thus, the changes in LASS and LASSindex after the first and second atrial fibrillation periods were not significantly different.

After cessation of the first atrial fibrillation period, left atrial preload and afterload remained unchanged from the values of 30.2±2.7 and 8.4±0.5 mm obtained before fibrillation. Similarly, mean aortic pressure, left ventricular systolic pressure, and LV dP/dt did not change from the respective values of 84±6 mm Hg, 100±4 mm Hg, and 1782±193 mm Hg/s after fibrillation. There were no statistical differences between the control values of any of these hemodynamic variables obtained before the first and second fibrillation periods or between the control values and the values obtained after the second atrial fibrillation period.

Metabolites in Atrial Myocardium
Figs 4Down, 5Down, and 6Down show the atrial tissue content of CrP, ATP, and lactate, respectively, during control conditions before atrial fibrillation, after 25 minutes of atrial fibrillation, and 30 minutes after cessation of fibrillation. The content of CrP in atrial myocardium was 4.5±0.5 mmol · kg ww-1 during control conditions and was slightly but significantly reduced during atrial fibrillation. After 25 minutes of atrial fibrillation, CrP had decreased to 3.4±0.4 mmol · kg ww-1 (P<.001). After 25 minutes of recovery after cessation of fibrillation, CrP returned to its control value. During atrial fibrillation, ATP and lactate did not change significantly from the respective control values of 2.9±0.2 and 2.6±0.3 mmol · kg ww-1 obtained before fibrillation. After 10 minutes of left atrial ischemia, however, the atrial tissue content of lactate increased to 9.2±0.9 mmol · kg ww-1.



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  		Figure 4. CrP concentration in atrial myocardial tissue before atrial fibrillation (control [Ctr]), after 25 minutes of fibrillation (AF), and 30 minutes after cessation of fibrillation (recovery [Rec]). *P<.05 versus value obtained before atrial fibrillation.



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  		Figure 5. ATP concentration in atrial myocardial tissue before atrial fibrillation, after 25 minutes of atrial fibrillation, and 30 minutes after cessation of fibrillation. Abbreviations as in Fig 4Up.



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  		Figure 6. Lactate concentration in atrial myocardial tissue before atrial fibrillation, after 25 minutes of atrial fibrillation, and 30 minutes after cessation of fibrillation. Isch indicates ischemia; other abbreviations as in Fig 4Up.


*    Discussion
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 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present study is the first to demonstrate that atrial dysfunction after cessation of atrial fibrillation is influenced by drugs that affect the L-type calcium channels. Atrial contractile dysfunction after cessation of short-term atrial fibrillation is reduced by verapamil but increased by BAY K8644. There is no apparent ischemia of the atrial myocardium during short-term atrial fibrillation.

Effects of Verapamil on Postfibrillation Atrial Dysfunction
Verapamil reduced both the magnitude and the duration of atrial hypocontractility after cessation of atrial fibrillation. The reduced postfibrillation atrial contractile dysfunction was most likely due to partial blockade of the L-type calcium channels by verapamil. Blockade of these channels probably reduces intracellular calcium overload in atrial myocytes during fibrillation.

A high depolarization rate is accompanied by elevated cytosolic calcium in vitro, both during pacing19 20 and during spontaneous tachycardia.33 An increase in cytosolic calcium also has been demonstrated with irregularity of depolarization.34 Like atrial fibrillation, ventricular fibrillation is characterized by frequent, irregular contractions, and an increase in intracellular calcium has been demonstrated in the fibrillating ventricle even in the absence of ischemia.22

Several factors may contribute to an increase in cytosolic calcium with increased depolarization frequency. At higher rates, both sodium and calcium influxes via L-type calcium channels are expected to be greater, because there are more action potentials per unit of time. The sarcoplasmic reticulum would be loaded with calcium at high rates and respond to a depolarization by an increased calcium release to the cytosol. Extrusion of calcium from the cell occurs mainly via the sodium-calcium exchanger. At high heart rates, however, both increased intracellular sodium and more positive membrane potentials tend to result in net calcium influx.35

An intracellular calcium overload may account for both the observed initial atrial hypercontractility and the ensuing period of atrial hypocontractility after cessation of atrial fibrillation. With a calcium overload in the fibrillating atrial myocytes, cytosolic calcium would be elevated the first few seconds after cessation of fibrillation, which would explain the brief, initial period of atrial hypercontractility that was observed. Transient exposure to high cytosolic calcium without ischemia induces distinctive contractile dysfunction,21 which was also observed after ventricular fibrillation in the study by Koretsune and Marban.22 Recent studies suggest that the contractile dysfunction observed after transient calcium overload is at least partly due to reduced calcium sensitivity,21 36 which probably resides at the level of the contractile proteins.37 38 The functional changes have been related to myofilament proteolysis, possibly of the thin-filament regulatory protein troponin I.37 39 Hence, a reduction in elevated cytosolic calcium during fibrillation by verapamil might be expected to diminish reduced calcium sensitivity after fibrillation.

Verapamil is a phenylalkylamine that antagonizes transsarcolemmal calcium influx by decreasing the open-time probability of the L-type calcium channels. This calcium antagonism is voltage and frequency dependent,25 26 and verapamil therefore would be expected to exert greater inhibition at the rapid atrial depolarizations during atrial fibrillation. Thus, reduced transient calcium overload during atrial fibrillation by pretreatment with verapamil might explain both the reduction in the initial, brief period of atrial hypercontractility and the reduction in the ensuing atrial hypocontractility observed in the present study.

Atrial contractility is influenced by atrial preload40 41 and afterload.42 43 In the present study, there were no changes in atrial preload or afterload (left atrial diameter and left ventricular segment length at the onset of atrial contraction) from before to after fibrillation either during control conditions or after pretreatment with verapamil. Furthermore, there were no changes in these variables during the periods of atrial hypercontractility and hypocontractility. The hypercontractile and hypocontractile phases of atrial contractility were also observed after ß-blockade in a previous study18 ; thus, changes in cardiac sympathetic stimulation are unlikely to explain our findings.

After injection of verapamil, there was a small decrease in mean arterial pressure, as would be anticipated from its vasodilatory effect. The small declines in left ventricular pressure and LV dP/dt are probably due to the negative inotropic effect of verapamil. However, because we observed no changes in left atrial afterload or preload after administration of verapamil, changes in left ventricular hemodynamics and peripheral vascular effects are unlikely to explain the effects of verapamil on postfibrillation atrial dysfunction. Moreover, atrial contractility remained unchanged after verapamil, probably because of a reflex sympathetic stimulation caused by the fall in arterial pressure.

Effects of BAY K8644 on Postfibrillation Atrial Dysfunction
BAY K8644 increased both the magnitude and the duration of atrial hypocontractility after cessation of atrial fibrillation. The increased postfibrillation atrial contractile dysfunction was most likely due to the agonistic effect of BAY K8644 on the L-type calcium channels, which probably leads to intracellular calcium overload in atrial myocytes during fibrillation. The dihydropyridine calcium channel agonist BAY K8644 binds to the L-type calcium channel in a state-independent and thereby voltage-independent manner,44 which favors a more prolonged open state of the channel and thereby increases the inward calcium current.44 45 Hence, BAY K8644 would be expected to promote the influx of calcium during each contraction in the fibrillating atrium. Thus, the detrimental effect of BAY K8644 on atrial contractility after fibrillation supports the hypothesis that intracellular calcium overload during atrial fibrillation is the mechanism for postfibrillation atrial dysfunction.

Intravenous administration of BAY K8644 produces an increase in arterial blood pressure, left ventricular systolic pressure, and peak positive LV dP/dt,46 as demonstrated in the present study. Atrial preload, however, was unaltered after BAY K8644 infusion. Moreover, BAY K8644 did not alter left ventricular segment length at the onset of atrial contraction.

During infusion of BAY K8644, there were no changes in atrial preload or afterload (left atrial diameter and left ventricular segment length at the onset of atrial contraction) from before to after fibrillation. Furthermore, there were no changes in these parameters during the periods of atrial hypercontractility and hypocontractility after fibrillation. Finally, the effect of BAY K8644 on postfibrillation contractile dysfunction cannot be ascribed to the effect of repetitive atrial fibrillation periods, as there was no significant difference in atrial dysfunction after the first and second fibrillation periods in the control group.

Metabolic Adjustments During Atrial Fibrillation
Atrial fibrillation is a high energy–demanding state, and it has been suggested that the gradual improvement in atrial contractile dysfunction after atrial fibrillation may represent the functional recovery of postischemic atrial myocardium.6 Both a brief increase in ventricular contractility23 and a period of ventricular hypocontractility, known as stunning,47 have been observed after ischemia. However, conflicting evidence exists as to whether atrial myocytes are ischemic during atrial fibrillation.48 49 Smetnev et al48 reported myocardial lactate production in the majority of patients with chronic atrial fibrillation and normal coronary angiography. In contrast, Lau et al49 found unchanged arterial and coronary sinus lactate concentrations after 5 minutes of induced atrial fibrillation in patients with paroxysmal atrial fibrillation. During atrial fibrillation, atrial blood flow increases twofold to threefold.50 Furthermore, the atrial vasodilator reserve is reduced but not abolished51 during atrial fibrillation. Thus, measurements of atrial blood flow have not established whether a relative atrial ischemia is present during atrial fibrillation.

The present study demonstrates that atrial dysfunction after cessation of short-term atrial fibrillation is not due to ischemia during the preceding fibrillation. During atrial fibrillation, ATP and lactate were unchanged from the control values obtained before and the recovery values obtained after atrial fibrillation. The small but significant decrease in CrP probably reflects the increased metabolism in the atrial myocardium during fibrillation. This assumption is supported by the fact that atrial oxygen consumption is increased during fibrillation.50

Clinical Implications
In patients, atrial fibrillation may be paroxysmal or chronic. Paroxysmal attacks may last for minutes or for days, and verapamil is widely used both in patients with paroxysmal and in those with chronic atrial fibrillation. The present data on short-term atrial fibrillation cannot be related to all patients without reservation, but a pharmacological agent that would safely improve contractile function of the atrial myocardium after fibrillation might be of clinical benefit.

It is presently unknown whether the same mechanism accounts for atrial contractile dysfunction after short-term, paroxysmal, and chronic atrial fibrillation. During chronic atrial fibrillation, Borgers et al52 demonstrated in a recent study that after 2 to 3 months of sustained atrial fibrillation in goats, 80% of the atrial myocardial cells had undergone dedifferentiation. There was loss of myofibrils, accumulation of glycogen, changes in mitochondrial size and shape, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These structural changes seen in atrial myocytes resemble those seen in chronic hibernating myocardium in humans, which is a condition in which elevated amounts of cytosolic calcium have been documented.53 In patients with chronic atrial fibrillation, degenerative changes and atrophy of the atrial myocytes, as well as interstitial fibrosis, have been described.54 55 Although such structural changes of the atrial myocardium may be reversible after cessation of fibrillation, it would take time to rebuild a normal contractile apparatus. This might explain the delay in recovery of atrial contractile function observed in patients after conversion of chronic atrial fibrillation. Another factor that may contribute to postfibrillation contractile dysfunction in patients with chronic atrial fibrillation is a depressed baroreflex sensitivity. However, no change in baroreflex function was observed in an experimental study after 6 weeks of atrial fibrillation.56

During the period of atrial contractile dysfunction after cardioversion of atrial fibrillation, thromboembolic complications have been reported to occur despite the absence of demonstrable atrial thrombi by transesophageal echocardiography performed before conversion.10 11 Because embolisms do not occur immediately but tend to occur over a period of days after cardioversion,10 57 it is reasonable to believe that thrombus formation develops because of the reduced contractility of the atrium after cardioversion.9 10 11 The present study shows that pretreatment with verapamil before atrial fibrillation reduces postfibrillation atrial dysfunction. Further studies are needed, however, to evaluate the possible pharmacological implications of this finding in patients with atrial fibrillation.

Conclusions
The present study demonstrates that atrial contractile dysfunction after short-term atrial fibrillation is reduced by pretreatment with the calcium antagonist verapamil, which suggests that transsarcolemmal calcium influx contributed to this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial contractile dysfunction. Atrial ischemia was not observed during fibrillation, which indicates that postfibrillation atrial dysfunction cannot be attributed to postischemic stunning in the present study.


*    Selected Abbreviations and Acronyms
 
CrP = creatine phosphate
LASS = left atrial systolic shortening
LASSindex = left atrial systolic shortening divided by atrial preload and expressed as a percent of the value obtained before atrial fibrillation
LV dP/dt = maximal positive first derivative of left ventricular systolic pressure


*    Acknowledgments
 
This work was supported by grants from the Anders Jahres Fund for the Promotion of Science, the Carl Sembs Fund, and legacies of the University of Oslo. We thank Hilde Hyldmo, Severin Leraand, and Turid Verpe for technical assistance and Sonja T. Flagestad and Heidi S. Kvalø for secretarial work.

Received July 12, 1995; revision received October 30, 1995; accepted November 15, 1995.


*    References
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