Paroxysmal atrioventricular block: are phase 3 and phase 4 block mechanisms or misnomers?

Abstract

The era of deductive analysis of the electrocardiogram was prolific in its ability to yield accurate inferences regarding the pathophysiology of a vast number of heart rhythm disorders. However, occasionally there was a tendency to infer hypothetical electrophysiological mechanisms without the benefit of direct cellular information. This turned out to be misleading in some cases in which suggested mechanisms were subsequently found to be incorrect, and it also unintentionally hampered the search for more basic mechanisms. Two cases in point are the use of the terms “phase 3” and “phase 4” block in reference to tachycardia-dependent (TD) and pause-dependent (PD) paroxysmal atrioventricular block (PAVB), respectively. Not only did basic studies definitely show that TD-PAVB is not related to phase 3 block, but also significant basic studies demonstrated that PD-PAVB need not depend on a phase 4 depolarization mechanism. Here we revisit the problems of TD- and PD-PAVB and illustrate by clinical and basic science examples possible pathophysiological mechanisms.

Figure 1

Electrocardiograms (ECGs) from a 65-year-old woman with a history of recurrent syncopal episodes showed normal sinus rhythm, complete left BBB pattern, and periods of Mobitz type II AV block. A: Electrophysiological study (EPS) showed intra-His bundle block with split His bundle potential (h₁, h₂) and a 5-ms increment of the h₁, h₂ interval before block. Intra-His bundle block was initially unrecognized because the h₁ deflection was overlooked. B: Rhythm strip 1 day later shows atrial tachycardia (rate 150–170 bpm) leading to TD-PAVB with 5.6-second ventricular asystole. AV conduction improved when the tachycardia slowed down (probably with a period of 2:1 AV block). Note the different time scale of the EPS recording.

Figure 2

Recordings from a 73-year-old woman with recurrent syncope. A: Selected recordings from a Holter ECG. The second and third strips are continuous recordings of lead I showing the development of PAVB with no apparent change in the atrial rate. Several such episodes developed during the 24-hour recording, while 1:1 AV conduction could be seen at other times at a faster atrial rate (top rhythm strip). B: Conduction system study obtained a week later when the patient presented with a stable 2:1 AVB. The recording shows a split His potential (H and H’) and intra-Hisian block on the His bundle electrogram (HBE). Notice the normal QRS duration.

Figure 3

Diagrammatic illustration of the responses of a normal ventricular myocyte action potential (AP, top) and a depressed AP (bottom) to premature stimulation. Top, so-called phase 3 or voltage-dependent refractoriness. The first stimulus (arrow) falls on an early phase 3 and fails to elicit a response. The second stimulus falls in late phase 3 and results in an abbreviated, slowly rising AP of low amplitude. The third stimulus that falls at the end of repolarization results in a full AP. The bottom recording illustrates postrepolarization refractoriness (arrows) in a depressed fiber. Because of delayed recovery of excitability, despite full repolarization after the second action potential, a depolarizing stimulus applied very early in diastole is incapable of bringing the cell to the threshold potential (broken horizontal line). Thus the stimulus fails, and only a subthreshold depolarization is seen. When a similar stimulus is applied later in diastole, the cell is activated after a substantial delay.

Figure 4

Ischemic canine proximal His-Purkinje system after ligation of the anteroseptal artery shows Mobitz type II block and TD-PAVB. Top, in vivo experiment; intracardiac His bundle electrograms from both left and right sides of the ventricular septum (Hb-L and Hb-R) showing a split His potential (H₁ and H₂). After the first two sinus beats, incremental atrial pacing started (P₁) resulting in 2:1 AVB followed by TD-PAVB in the His bundle. Bottom, in vitro recordings from an ischemic His-Purkinje preparation. Inset, arrangement of electrodes: stimuli applied to proximal His bundle (S); intracellular recording electrode in penetrating portion of His bundle (Hb). Note the slow approach to threshold preceding each action potential (foot potentials) as a result of slow conduction through the bundle; extracellular bipolar recordings from proximal right (Rb) and left (Lb) bundles. A: 1:1 conduction from His bundle to both bundle branches (arrows point at the extracellular recording spikes) at a slow driving rate (40/min). B: Increasing the rate to 75/min resulted in 3:2 response with slight (6 ms) increment of Hb-Lb conduction time before the blocked beat. The Hb recording showed only a local potential during block. C: Further increase of the rate to 111/min resulted in complete conduction failure; the Hb recording showed repetitive local potentials with failure of inscription of a regenerative action potential. Note that conduction failure occurred at cycle lengths (CLs) that far exceeded the action potential duration (i.e., postrepolarization refractoriness). The Rb and Lb electrograms have been retouched for clarity. (Reprinted with permission of the American College of Cardiology from El-Sherif et al, Am J Cardiol 1974;35:421– 434).

Figure 5

A: Clinical case of pause-dependent paroxysmal AV block. A brief period of complete AV block with idioventricular escape rhythm was initiated by a long atrial cycle that followed the atrial premature beat marked X. On the right, 1:1 AV conduction resumed on slight acceleration of the sinus rate. Note the marked degree of sinus arrhythmia associated with AV block and resumption of normal conduction. B and C: Armchair model used by Singer, Lazzara, and Hoffman to illustrate their idea of phase 4 block. Panels represent transmembrane potentials from a Purkinje cell (top) and simultaneously recorded surface electrogram (bottom). B: Left, transmembrane action potential recorded during stimulation at a rate sufficiently fast to suppress phase 4 depolarization. Right, normal action potential initiated at −90 mV (response A) followed by a premature response initiated during repolarization at −60 mV (response B). The latter had decreased amplitude and upstroke velocity, as well as reduced rate of propagation as indicated by aberration of electrogram. C: Left, normal action potential and ECG complex. Right, the subsequent action potential is initiated in same fiber after development of phase 4 depolarization at the same level of membrane potential (C) as the premature response; its amplitude, upstroke velocity, and speed of propagation are expected to be reduced, and the ECG is expected to be aberrant (modified with permission of the American Heart Association, Inc., from Singer DS, et al, Circ Res 1967;21:537–558).

Figure 6

Influence of diastolic depolarization versus hyperpolarization on conduction in a heterogeneous Purkinje fiber bundle placed in a three compartment tissue bath. Sucrose superfusion of the middle segment. The two outer fiber segments were superfused with normal Tyrode’s solution, stimulation was applied to the proximal segment (P), and activity was recorded from P and from the distal segment (D). Three superimposed recordings are shown. Top traces, P; middle traces, D; bottom traces dV/dt of D. In all sweeps, the initial action potential is the last of a series of 10 evoked in P at BCL = 500 ms. At this rate, complete PD block occurred, and only subthreshold depolarizations were apparent in the distal segment. A postmature action potential initiated in P after 1850 ms activated the distal fiber after 141 ms (discharge A). This long delay occurred despite the large amplitude (89 mV) and dV/dt max (475 V/s) of the distal action potential. In the next sweep, application of a slow depolarizing current ramp to D increased its slope of phase 4 depolarization. When, at the end of the ramp, the proximal segment was stimulated, propagation was again successful, but at a much reduced P-D conduction time (59 ms). Rapid propagation occurred even though the amplitude and dV/dt of phase 0 were significantly decreased in the distal segment, as a result of a reduction of the takeoff potential. In contrast, when the slope of phase 4 was inverted by the application of a hyperpolarizing ramp, complete block was induced (C), and only the electrotonic image of the proximal action potential was apparent in the distal trace. (Reproduced with permission of the American Heart Association from Jalife J, et al, Circulation 1983;67:912–922).

Figure 7

PD conduction block in an isolated false tendon (dog) exposed to 20 mM KCL Tyrode’s solution. Top trace obtained from cell close to stimulation site; middle trace, from center of the bundle; and bottom trace, recorded more distally. At BCL = 1500 ms all impulses were blocked before they reached the middle segment. Successful activation of that segment was obtained when the stimulus interval was reduced to 500 ms. However, block persisted at the distal segment (reproduced with permission of the American Heart Association from Jalife J, et al, Circulation 1983;67:912–922).

Figure 8

Coexistence of TD and PD block of slow responses in a depressed dog cardiac Purkinje fiber exposed to 20 mM KCl and 9 mM CaCl₂ and stimulated at a BCL of 2000 ms. Premature stimuli were applied every tenth beat with an increasing delay to scan the diastolic interval. The superimposed records in all three panels were recorded within 3 minutes. The upper record (labeled P) in each of them corresponds to a site proximal to the bipolar stimulating electrode; the lower record (labeled D), to a site 12 mm apart. A: Early premature slow responses are blocked before they reach the distal recording. B: Slow responses initiated at intermediate intervals propagate throughout the fiber. C: Slow responses initiated very late in diastole are unable to propagate through the fiber. See text for details.