Characterization of Low Right Atrial Isthmus as the Slow Conduction Zone and Pharmacological Target in Typical Atrial Flutter

Patient Characteristics

Forty-four patients, 20 with paroxysmal supraventricular tachycardia (group 1) and 24 with clinically documented paroxysmal typical atrial flutter (group 2), were included. Group 1 had 11 men and 9 women; their mean age was 54±11 years (range, 39 to 72 years). Group 2 had 14 men and 10 women; their mean age was 56±16 years (range, 15 to 80 years). All patients were refractory to or intolerant of a mean of 3±1 (range, 2 to 5) antiarrhythmic drugs before referral. Ten patients had associated cardiovascular diseases, including rheumatic heart disease (n=1), hypertension (n=4), coronary heart disease (n=3), and mitral valve prolapse (n=2).

Catheter Positions

Each patient gave informed consent. Research protocols were approved by the Human Research Committee at this institution. As described previously, all antiarrhythmic drugs were discontinued for at least five half-lives before the study.¹⁷ Both the orifices of the inferior vena cava and coronary sinus were identified by venograms. In all patients, a 7F, 20-pole, deflectable “halo” catheter with 10-mm paired spacing (Cordis-Webster) was positioned around the tricuspid annulus to record the right atrial activation in the lateral wall and the low right atrial isthmus simultaneously. We tried to put the distal tip of halo catheter into the coronary sinus and let the electrode poles 1,2 (H1) be located at the ostium in each patient (Fig 1A⇓ and 1B⇓). If the halo catheter could not be placed into the coronary sinus, it was adjusted with the distal tip against the septum, and poles 1,2 (H1) were located close to the ostium of the coronary sinus in the left anterior oblique (LAO) view. In the present study, the halo catheter could be placed into the coronary sinus in 32 of the 44 patients (14 of 20 group 1 and 18 of 24 group 2 patients). A 7F, deflectable, decapolar catheter with 2-mm interelectrode distance and 5-mm space between each electrode pair was also inserted into the coronary sinus via the internal jugular vein. Position of the proximal electrode pair at the ostium of the coronary sinus was confirmed with contrast injection. Three multipolar, closely spaced (interelectrode space, 2 mm) electrode catheters with a deflectable tip (Mansfield Division of Boston Scientific Inc) were introduced from the right and left femoral veins and placed in the high right atrium, low right atrium (entrance of the low right atrial isthmus), and His bundle area for recording and pacing.

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Figure 1.

Radiographs in the right anterior oblique projection (A) and left anterior oblique (LAO) projection (B) show the positions of the “halo” catheter and multielectrode catheters in the low right atrium (LRA), coronary sinus (CS), and His bundle region (HBE). The orifice of inferior vena cava was delineated by dashed line. In the LAO view, H1 is located at the ostium of the coronary sinus, H2 through H5 are located within the low right atrial isthmus, and H6 through H10 are located within the free wall. The sparing distances of H1 to H2, H2 to H4 and H4 to H5 represent the lengths of septal, middle, and lateral isthmuses, respectively. H1 represents the distal electrode poles (1,2), and H10 represents the proximal electrode poles (19,20).

Baseline Electrophysiological Study

Each patient underwent a baseline electrophysiological study in the fasting, unsedated state. None of the patients had an episode of sustained atrial flutter shortly before entering the study. A programmed digital stimulator (DTU-210 or 215, Bloom Associate Ltd) was used to deliver electrical impulses of 2.0 ms in duration at 10-mA current. The study protocol included (1) incremental pacing from the low right atrium and ostium of the coronary sinus at pacing cycle lengths of 500, 450, 400, 350, 300, and 250 ms to measure the conduction time in the low right atrial isthmus and lateral wall; (2) burst atrial pacing from the above sites at progressively shorter cycle lengths until 2:1 atrial capture to induce atrial flutter; (3) atrial pacing using the cycle length equal to flutter cycle length to compare the conduction time in the low right atrial isthmus if typical atrial flutter was induced; and (4) single extrastimulus testing with 300-ms drive cycle length at the above pacing sites and high right atrium to determine the atrial effective refractory periods.

Intracardiac bipolar electrograms were displayed simultaneously with ECG leads V₁ and V_II or aVF on a multichannel oscilloscopic recorder (model VR-13, PPG Biomedical System, Cardiovascular Division) and were recorded on paper at a speed of 200 mm/s. The filter was set from 30 to 500 Hz. Measurement of electrograms was made with the onset of the first sharp component that reached an angle of 45° with the baseline. In the LAO view, the electric pairs located in the medial sites of the right atrium–inferior vena cava junction were considered located within the isthmus, while those located in the lateral sites of the right atrium-inferior vena cava junction were considered located within the lateral wall. Therefore, the relevant conduction velocity could be calculated by measuring the respective conduction time and sparing distance between two end dipoles within the isthmus and lateral wall. In the Fig 1B⇑, the H1 electrode pair is located at the ostium of the coronary sinus, H2 through H5 electrode pairs are located within the low right atrial isthmus, and H6 through H10 electrode pairs are located within the lateral free wall. Conduction velocity in the low right atrial isthmus was measured from the septal portion to lateral portion (H1 to H5) and from the lateral portion to septal portion (H5 through H1) during pacing from the coronary sinus ostium and low lateral right atrium (near the H6 electrode pair), respectively. Conduction velocity in the lateral wall (H6 through H10) was measured only during pacing from the low right atrium (near the H6 electrode pair), because activation of the lateral free wall during pacing from the coronary sinus ostium represents bidirectional conduction via the interatrial septum and low right atrial isthmus with collision of wave fronts in the midlateral free wall.

Pharmacological Study

Each group was further divided into two subgroups. After the baseline study, groups 1A and 2A received intravenous loading infusion of procainamide 15 mg/kg at a rate not exceeding 50 mg/min, followed by a maintenance infusion of 2 mg/min; groups 1B and 2B received intravenous infusion of dl- sotalol 1.5 mg/kg over 10 minutes.^{18 19} The electrophysiological study protocol and measurement were repeated to observe the pharmacological effects on the flutter reentrant circuit.

Definitions

The low right atrial isthmus was defined as a path formed by the orifice of the inferior vena cava, eustachian valve/ridge, coronary sinus ostium, and tricuspid annulus. Thus, the septal portion (1 cm lateral to the coronary sinus ostium) of the isthmus is contiguous to the posterior triangle of Koch.^{5 20 21} The lateral portion (1 cm medial to the orifice of inferior vena cava) of the isthmus merges into the pectinate muscles. The residual part of the isthmus was defined as the middle portion (Fig 1B⇑). Counterclockwise (typical) atrial flutter was defined as an atrial flutter with craniocaudal activation of the anterior and lateral walls of the right atrium and caudocranial activation of the atrial septum, inverted P waves in the inferior leads, and positive P wave in lead V₁. Clockwise atrial flutter was defined as an atrial flutter with a similar flutter cycle length and reverse activation sequence of the counterclockwise flutter. Atypical atrial flutter was defined as an atrial flutter other than the counterclockwise and clockwise atrial flutters.

Statistical Analysis

Quantitative values are expressed as mean±SD. Student’s paired t test was used for statistical comparison of the conduction velocity and effective refractory periods before and after infusion of antiarrhythmic drugs and for comparison of conduction velocity at 500 ms versus other pacing cycle lengths. Student’s unpaired t test was used for statistical comparison of conduction velocity, effective refractory periods, and drug responses between groups 1 and 2. Statistical analysis of conduction velocity in the septal, middle, and lateral isthmus was performed with the use of ANOVA test. χ² test and Fisher’s exact test were used for analysis of relationship between the pacing site and type of atrial flutter. A value of P<.05 was considered statistically significant.

Group 1

Conduction Velocity

Conduction velocity from the septal isthmus to the lateral isthmus during pacing from the coronary sinus ostium and from lateral isthmus to septal isthmus during pacing from the low lateral right atrium at 500-, 450-, 400-, 350-, 300-, and 250-ms drive cycle lengths was significantly lower than that in the lateral wall during pacing from the low lateral right atrium before and after infusion of antiarrhythmic drugs (Figs 2A⇓, 2B⇓, 3A⇓, and 3B⇓). Conduction velocity in the lateral isthmus (0.842±0.045 and 0.886±0.051 m/s) during atrial pacing from the low right atrium and coronary sinus ostium at 250-ms cycle length was significantly higher than that in the middle (0.382±0.044 and 0.396±0.047 m/s) and septal (0.345±0.040 and 0.352±0.039 m/s) isthmus (P<.05). Procainamide significantly decreased the conduction velocity at all pacing cycle lengths in the isthmus and lateral wall in group 1A (Fig 2A⇓ and 2B⇓), but sotalol did not change the conduction velocity at any pacing cycle length in group 1B (Fig 3A⇓ and 3B⇓).

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Figure 2.

Conduction velocity in the right atrial free wall (FW) and low right atrial isthmus (IS) during different pacing cycle lengths in the baseline state and after infusion of procainamide (group 1A). A, Results from coronary sinus ostial pacing; B, results from low right atrial pacing. *P<.05, baseline vs procainamide; †P<.05, 500 ms vs other pacing cycle lengths.

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Figure 3.

Conduction velocity in the right atrial free wall (FW) and low right atrial isthmus (IS) during different pacing cycle lengths in the baseline state and after infusion of sotalol (group 1B). A, Results from coronary sinus ostial pacing; B, results from low right atrial pacing. †P<.05, 500 ms vs other pacing cycle lengths.

Effective Refractory Period

At the baseline study, the effective refractory period at the coronary sinus ostium was significantly longer than that at the high and low right atrium (group 1A, 194±21 versus 175±23 versus 183±26 ms; group 1B, 198±20 versus 181±23 versus 187±22 ms; P<.05). Procainamide significantly prolonged the atrial effective refractory periods in group 1A (high right atrium, 201±31 ms, +15±6%; low right atrium, 212±24 ms, +16±6%; coronary sinus ostium, 217±25 ms, +12±5%), and sotalol significantly prolonged the effective refractory period in group 1B with a higher extent (high right atrium, 222±32 ms, +22±5%; low right atrium, 225±30 ms, +20±7%; coronary sinus ostium, 236±25 ms, +19±6%) (Fig 4A⇓ and 4B⇓).

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Figure 4.

Graphs demonstrate the effective refractory periods of the high right atrium (HRA), low right atrium (LRA), and proximal coronary sinus (PCS) in the baseline state (open bars) in group 1 patients. Infusion of procainamide (group 1A) or sotalol (group 1B) significantly increases the atrial refractory periods (hatched bars). *P<.05.

Induction of Atrial Flutter

In group 1A, incremental pacing from the low lateral right atrium reproducibly induced clockwise atrial flutter in 2 patients after counterclockwise wave front produced gradual conduction delay with block in the middle portion of the isthmus (Fig 5A⇓). The flutter cycle lengths in these 2 patients were 200 ms. After procainamide infusion, clockwise atrial flutter was still induced. Both flutter cycle lengths were prolonged; one was 245 ms (+30 ms in the isthmus and +15 ms in the residual atrial wall), and the other was 260 ms (+40 ms in the isthmus and +20 ms in the residual atrial wall). Thus, most of the increase in cycle length was due to an increase in conduction time in the low right atrial isthmus. Incremental pacing from the coronary sinus ostium induced counterclockwise atrial flutter in 4 patients after a clockwise wave front produced gradual conduction delay with block in the septal portion of the isthmus (Fig 5B⇓). The mean flutter cycle length was 220±15 ms. After procainamide infusion, counterclockwise atrial flutter was still induced with the same activation sequence in these 4 patients. The flutter cycle length was prolonged to 278±21 ms. One cycle length was prolonged to 340 ms, and 1: 1 AV conduction with acceleration of ventricular response occurred. There was more prolongation of conduction time (50±10 ms) in the isthmus than in the residual atrial wall (18±12 ms).

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Figure 5.

A, Incremental pacing from the low lateral right atrium (near H6 and H7) using a cycle length of 210 ms produced gradual conduction delays and block in the isthmus (between H4 and H2) of the counterclockwise wave front and initiated clockwise atrial flutter. B, Incremental pacing from the coronary sinus ostium (OCS) using a cycle length of 180 ms produced gradual conduction delays and block in the isthmus (between H1 and H2) of the clockwise wave front, and initiated counterclockwise atrial flutter. HBE indicates recordings at the His bundle area; PCS: recordings at the proximal coronary sinus.

In group 1B, incremental pacing from the low lateral right atrium induced clockwise atrial flutter in 2 patients. One flutter cycle length was 245 ms and the other was 220 ms. After sotalol infusion, clockwise atrial flutter was not induced. Incremental pacing from the coronary sinus ostium induced counterclockwise atrial flutter in another 3 patients. The mean flutter cycle lengths was 197±12 ms. After sotalol infusion, counterclockwise atrial flutters were still induced with the same activation sequence, but mean cycle length was slightly prolonged to 207±12 ms. The increase in flutter cycle length was due to an increase in conduction time (13±6 ms) in the low right atrial isthmus without conduction delay in the residual atrial wall.

Direct induction of counterclockwise and clockwise atrial flutter was documented in 22 of 25 episodes (88%) in 9 patients, and 3 episodes (12%) had transitional atrial fibrillation induced by short pacing cycle length (190±26 ms). Eight episodes of clockwise atrial flutter were all induced from the low lateral right atrium, while 14 episodes of counterclockwise atrial flutter were all induced from the coronary sinus ostium. Thus, there was significant correlation between the pacing site and type of atrial flutter (P<.001).

Group 2

Conduction Velocity

Conduction velocity from the septal isthmus to the lateral isthmus during pacing from the coronary sinus ostium and from the lateral isthmus to the septal isthmus during pacing from the low lateral right atrium at 500-, 450-, 400-, 350-, 300-, and 250-ms drives was significantly lower than that in the lateral wall during pacing from the low lateral right atrium before and after infusion of antiarrhythmic drugs (Figs 6A⇓, 6B⇓, 7A⇓ and 7B). Conduction velocity in the lateral isthmus (0.769±0.038 and 0.782±0.044 m/s) during atrial pacing from the low right atrium and coronary sinus ostium at the 250-ms cycle length was significantly higher than that in the middle (0.336±0.045 and 0.341±0.046 m/s) and septal (0.297±0.033 and 0.315±0.042 m/s) isthmus (P<.05). Procainamide significantly decreased the conduction velocity at all pacing cycle lengths in the isthmus and lateral wall in group 2A (Fig 6A⇓ and 6B⇓), but sotalol infusion significantly decreased the conduction velocity only at pacing cycle lengths of 300 and 250 ms in group 2B (Fig 7A⇓ and 7B⇓).

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Figure 6.

Conduction velocity in the right atrial free wall (FW) and low right atrial isthmus (IS) during different pacing cycle lengths in the baseline state and after infusion of procainamide (group 2A). A, Results from coronary sinus ostial pacing; B, results from low right atrial pacing. *P<.05, baseline vs procainamide; †P<.05, 500 ms vs other pacing cycle lengths.

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Figure 7.

Conduction velocity in the right atrial free wall (FW) and low right atrial isthmus (IS) during different pacing cycle lengths in the baseline state and after infusion of sotalol (group 2B). A, Results from coronary sinus ostial pacing; B, results from low right atrial pacing. *P<.05, baseline vs sotalol; †P<.05, 500 ms vs other pacing cycle lengths.

Effective Refractory Period

At baseline study, the effective refractory period at the coronary sinus ostium was significantly longer than that at the high and low right atriums (group 2A, 210±34 versus 160±25 versus 165±24 ms; group 2B, 202±16 versus 164±22 versus 177±18 ms; P<.05). Procainamide significantly prolonged the atrial effective refractory periods in group 2A (high right atrium, 186±27 ms, +16±5%; low right atrium, 194±30 ms, +18±5%; coronary sinus ostrum, 237±40 ms, +13±5%), and sotalol significantly prolonged the effective refractory period in group 2B to a higher extent (high right atrium, 208±22 ms, +27±7%; low right atrium, 219±21 ms, +25±6%; coronary sinus ostium, 241±18 ms, +20±7%) (Fig 8A⇓ and 8B⇓).

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Figure 8.

Effective refractory periods of the high right atrium (HRA), low right atrium (LRA), and proximal coronary sinus (PCS) in the baseline state (open bars) in group 2 patients. Infusion of procainamide (group 2A) or sotalol (group 2B) significantly increases the atrial refractory periods (hatched bars). *P<.05.

Induction of Atrial Flutter

In group 2A, incremental pacing from the coronary sinus ostium induced clinical counterclockwise atrial flutter in all patients after a clockwise activation wave front produced gradual conduction delay with block in the septal or middle portion of the isthmus. The mean flutter cycle length at baseline study was 246±27 ms. Conduction time (96±14 ms) in the low right atrial isthmus accounted for 40±8% of the flutter cycle length. Conduction time in the low right atrial isthmus during pacing from the low lateral right atrium using a cycle length equal to that of typical flutter was 90±12 ms. Incremental pacing from the low lateral right atrium could induce counterclockwise atrial flutter in 2 patients and clockwise atrial flutter in 6 patients. The mean cycle length of the clockwise atrial flutter was 238±19 ms. After procainamide infusion, pacing from the coronary sinus ostium still induced all the counterclockwise atrial flutters with prolongation of the flutter cycle length to 320±35 ms. Procainamide also increased conduction time in the low right atrial isthmus during atrial flutter (128±15 ms) and atrial pacing (116±12 ms). The increase in conduction time in the low right atrial isthmus accounted for 52±19% of the increase in flutter cycle length. Furthermore, 5 patients (42%) had gradual conduction delay in the isthmus, culminating in conduction block and termination of counterclockwise atrial flutter (Fig 9A⇓ and 9B⇓). After procainamide infusion, low lateral right atrial pacing still induced clockwise atrial flutter in 6 patients with prolongation of mean cycle length to 308±35 ms.

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Figure 9.

A case of typical atrial flutter terminated by intravenous infusion of procainamide. Intermittent bundle branch block was noted during the baseline study. A, In the baseline state, the conduction time between H1 and H3 (within the isthmus) during flutter is 40 ms. B, After infusion of procainamide, the conduction time between H1 and H3 prolongs to 80 ms. The last beat of atrial flutter blocks between H1 and H2. HBE indicates His bundle region; OCS, coronary sinus ostium; and FCL, flutter cycle length.

In group 2B, incremental pacing from the coronary sinus ostium induced clinical counterclockwise atrial flutter in all patients after a clockwise activation wave front produced gradual conduction delay with block in the low right atrial isthmus. The mean flutter cycle length at baseline study was 240±22 ms. Conduction time (95±15 ms) in the low right atrial isthmus accounted for 42±6% of the flutter cycle length. Conduction time in the low right atrial isthmus during pacing from the low lateral right atrium using a cycle length equal to that of typical flutter was 89±14 ms. Incremental pacing from the low lateral right atrium also induced counterclockwise atrial flutter in 1 patient and clockwise atrial flutter in 5 patients. The cycle lengths of the clockwise atrial flutter were 230±15 ms. After sotalol infusion, pacing from the coronary sinus ostium induced counterclockwise atrial flutters in only 6 patients without significant prolongation of the flutter cycle length (248±20 ms). Sotalol did not significantly increase conduction time in the low right atrial isthmus during atrial flutter (96±12 ms) and atrial pacing (90±18 ms), nor did it produce spontaneous termination of counterclockwise atrial flutter in any patient. After sotalol infusion, pacing from the low lateral right atrium did not induce counterclockwise or clockwise atrial flutter but induced atypical atrial flutter in another 2 patients.

Direct induction of counterclockwise and clockwise atrial flutter was documented in 43 of 50 episodes (86%) in 24 patients, and 7 episodes (14%) had transitional atrial fibrillation induced by a short pacing cycle length (186±24 ms). All of the 16 episodes of clockwise flutter (100%) were induced from the low lateral right atrium, while 22 of 27 episodes (82%) of counterclockwise flutter was induced from the coronary sinus ostium. Thus, there was significant correlation between the pacing site and type of atrial flutter (P<.001).

Comparisons Between Groups 1 and 2

Group 2 patients had a lower conduction velocity at all paced cycle lengths in the low right atrial isthmus and a shorter effective refractory period at the high and low right atrium than group 1 patients (Figs 10⇓ and 11⇓). There was no significant difference in response to procainamide with respect to conduction velocity and effective refractory period between the two groups. Comparing groups 1 and 2 shows no significant difference in the effects of sotalol on effective refractory period, while sotalol decreased conduction velocity in the isthmus at short drive cycle lengths in group 2 but not in group 1 patients.

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Figure 10.

Comparison of conduction velocity in the right atrial free wall (FW) and low right atrial isthmus (IS) during different pacing cycle lengths between groups 1 and 2. A, Results from coronary sinus ostial pacing; B, results from low right atrial pacing. *P<.05, group 1 vs 2.

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Figure 11.

Comparison of effective refractory periods of the high right atrium (HRA), low right atrium (LRA), and proximal coronary sinus (PCS) in the baseline state between group 1 (open bars) and 2 (hatched bars) patients. *P<.05, group 1 vs 2.

Major Findings

The present study was the first to demonstrate that incremental pacing from the low lateral right atrium and coronary sinus ostium during sinus rhythm produced rate-dependent conduction delays in the low right atrial isthmus, especially the middle and septal isthmus contiguous to the posterior triangle of Koch. Furthermore, gradual conduction delay with unidirectional block in the isthmus was relevant to development of counterclockwise and clockwise atrial flutters. Patients with clinical atrial flutter had much slower conduction in the low right atrial isthmus and shorter effective refractory periods in the right atrium than those without clinical flutter. The prolongation of atrial flutter cycle length after procainamide infusion was due to a predominant increase of conduction time in the low right atrial isthmus. In contrast, sotalol had less effect on atrial flutter cycle length and slow conduction zone, although it produced a greater prolongation in atrial effective refractory period.

Role and Site of Slow Conduction in Atrial Flutter

Klein et al¹ have performed intraoperative atrial epicardial mapping during common atrial flutter in 2 patients and reported that relatively slow conduction was found at the low right atrial tissue between the tricuspid valve ring and the orifices of the inferior vena cava and proximal coronary sinus, respectively. Saumarez et al²⁰ used multielectrode endocardial mapping preoperatively and demonstrated slow, tortuous conduction in the “mouth“ of the Koch’s triangle associated with common atrial flutter. Olshansky et al¹⁵ showed slow conduction associated with fractionated electrogram and missing interval of electrical activity during human type I atrial flutter in the inferior right atrium using endocardial catheter mapping and pacing techniques. Cosio et al⁸ and Chen et al¹⁶ also used entrainment pacing in the IVC-TA isthmus to show rate-dependent conduction delays in orthodromic activation during human common atrial flutter. In the present study, incremental pacing from the low lateral right atrium and coronary sinus ostium during sinus rhythm produced rate-dependent conduction delays in the low right atrial isthmus, especially near the posterior triangle of Koch (middle and septal isthmus). Furthermore, atrial pacing resulted in unidirectional conduction block in the low atrial isthmus and then induced counterclockwise or clockwise atrial flutter in patients with or without clinical atrial flutter. These findings proved that the low right atrial isthmus has slow conduction properties and it is critical to development of the human atrial flutter.

The mechanism of slow conduction in the isthmus was not clear. Spach et al²² have demonstrated that conduction velocity of atrial impulses is faster parallel to the long axis of myocyte fibers and slower along the plane transverse to myocyte fiber orientation. This phenomenon was explained by higher axial resistance caused by scant cell-to-cell coupling encountered when impulses propagated perpendicular to the long axis of muscle fibers.^{22 23} With aging or atrial dilatation, intercellular fibrosis can change the density of gap junctions and produce nonuniform anisotropic conduction through the trabeculations of the low right atrial isthmus.²³ This hypothesis is supported by histological analysis of slow conduction areas during atrial flutter in animal models. Boineau et al¹² have concluded that fiber directions, packing density, and dimensions of groups of fibers exerted a significant influence on the conduction velocity.

Atrial Properties in Patients With Clinical Atrial Flutter

Rensma et al²⁴ have shown that induction of rapid repetitive responses, atrial flutter and atrial fibrillation in normal dogs was closely related to the wavelength of the initiating premature impulse. The wavelength of an impulse is defined as the product of conduction velocity and refractory period. They found that most of atrial flutter was induced at a critical wavelength between 9.7 and 7.8 cm.²⁴ Josephson,²⁵ Attuel et al,²⁶ and Buxton et al,²⁷ have systematically measured atrial refractory periods in patients with a history of atrial flutter and/or fibrillation and compared them with control subjects. The results of these series revealed that atrial refractory periods in patients with atrial flutter and/or fibrillation were significantly shorter than those of control subjects. Furthermore, when compared with control subjects, patients with a history of atrial flutter could manifest an exaggerated degree of intraatrial conduction delay in response to premature stimulation over a greater zone of coupling intervals. Papageorgiou et al²¹ also reported that atrial premature stimulation from high right atrial lateral wall induced much more fractionation and conduction delay in the posterior triangle of Koch than distal coronary sinus stimulation in patients with induced atrial fibrillation. In the present study, group 2 patients (with clinical typical atrial flutter) had a lower conduction velocity in the low right atrial isthmus (especially at the middle and septal portions) and a shorter effective refractory period at the high and low right atrium than group 1 patients (without clinical atrial flutter). These findings confirmed the previous studies and supported the hypothesis that slow conduction and short refractory periods may foster the initiation of atrial flutter in the human right atrium by allowing the establishment of a sufficiently short critical wavelength.

Pharmacological Effects on Atrial Flutter

In the animal model of Y-shaped atrial lesion, Wu and Hoffman²⁸ have reported that procainamide could terminate sustained atrial flutter around the tricuspid ring. Termination was preceded by a marked increase in cycle length and correlated with depression of conduction rather than prolongation of refractoriness. In the canine sterile pericarditis model, Schoels et al²⁹ have shown that procainamide slowed conduction in the slow zone of atrial flutter more than it prolonged refractoriness. Termination of circus movement atrial flutter was typically preceded by a large increase in cycle length, which predominantly resulted from further slowing of conduction in the slow zone. Thus, they concluded that procainamide has differential effects on the components of the reentrant pathway. Stambler et al¹⁸ used antiarrhythmic drugs to characterize the human type I atrial flutter. Although they did not measure the conduction velocity in the area of slow conduction, they found that the increase in atrial flutter cycle length induced by procainamide was significantly greater than the increase in monophasic action potential duration; furthermore, a change in atrial flutter cycle length did not correlate with a change in monophasic action potential. In the present study, procainamide decreased conduction velocity predominantly in the low right atrial isthmus during atrial flutter and atrial pacing, and the increase in conduction time in the isthmus accounted for 52±19% of the increase in flutter cycle length. Furthermore, procainamide produced gradual conduction delay, culminating in conduction block in the isthmus and termination of the typical atrial flutter. In contrast, procainamide only prolonged the atrial effective refractory periods by 12% to 18%. Therefore, these finding suggested that procainamide might terminate human type 1 atrial flutter by causing failure of impulse propagation through the low right atrial isthmus, although other mechanisms might also play a role. Furthermore, a possible explanation for failure of wave-front propagation would be a reduction in safety factor for conduction as suggested by Cha et al³⁰ in their animal model of atrial flutter.

Spinelli and Hoffman³¹ and Boyden and Graziano³² have shown that d-sotalol slightly prolonged the flutter cycle length (+10% to +15%) and terminated atrial flutter by producing complete conduction block of the reentering impulse within the critical area or inducing failure of the lateral boundary of the circuit path in the canine model of Y-shaped atrial lesion. In the tricuspid regurgitation model of atrial flutter, Boyden³³ has demonstrated another mode of termination by d-sotalol, which was preceded by a prolongation and then a period of shortened atrial cycle lengths; ie, the regular reentrant activity of the flutter rhythm became unstable (fibrillatory) in the presence of d-sotalol. In the crush injury model of atrial flutter, Feld et al³⁴ and Inoue et al³⁵ have suggested that the class III antiarrhythmic drugs (including d-sotalol and E-4031) selectively prolonged atrial refractoriness with little effect on conduction velocity or flutter cycle length, and they were highly effective in termination and suppression of atrial flutter by abolishing the excitable gap and eliminating the dispersion of refractoriness. However, in a randomized human study, intravenous infusion of d,l-sotalol (1.0 to 1.5 mg/kg) was not effective in converting atrial flutter to sinus rhythm, while intravenous ibutilide (a pure class III agent) was very effective in terminating atrial flutter.^{19 36} In the present study, d,l-sotalol did not significantly decrease conduction velocity in the low right atrial isthmus during atrial flutter, nor produce spontaneous termination of the typical atrial flutter although it significantly prolonged the atrial refractory periods by 19% to 27%. In contrast, it could prevent reinduction of the typical atrial flutter in 6 patients. Furthermore, several studies have shown that sotalol was effective in preventing the recurrence of atrial flutter after patients had restored sinus rhythm previously.^{37 38 39}

Study Limitations

The atrial refractory periods were not determined during atrial flutter and might be overestimated. However, the drive cycle length of 300 ms is close to the flutter cycle length, and the difference may be small. Because some patients with clinical atrial flutter required high current (10 mA) electric stimulation for induction of tachycardia, we used this intensity of electric impulses to perform atrial pacing for measurement of conduction velocity and effective refractory period. Papageorgiou et al²¹ reported that atrial fibrillation was more readily inducible by premature stimulation from the high right atrium than the distal coronary sinus because of increased anisotropy in Koch’s triangle. However, in the present study, atrial flutter was more readily induced by rapid pacing from the low right atrium and coronary sinus ostium. Whether different pacing sites and pacing modes result in different electrophysiological characteristics that are related to the type of atrial tachyarrhythmia is unknown and deserves further study.

Conclusions

The low right atrial isthmus near the posterior triangle of Koch is the anatomic slow conduction zone during typical atrial flutter. Gradual conduction delay with unidirectional block in this isthmus was relevant to initiation of counterclockwise and clockwise atrial flutter. Procainamide prolongs the atrial flutter cycle length by predominantly diminishing conduction velocity in the slow conduction zone and terminates atrial flutter by inducing conduction block in the low right atrial isthmus. Sotalol prolongs the atrial flutter cycle length minimally by increasing atrial refractoriness but cannot terminate atrial flutter; however, it can prevent reinduction of atrial flutter.