Certain pitfalls are inherent in the use of His bundle recordings for the diagnosis of VT, as described in the following paragraphs.

(1) The inability to record His bundle potentials during the tachycardia most commonly reflects improper catheter position; therefore, verification of proper catheter position is mandatory. The simplest methods for verifying proper catheter position include the following: (a) the immediate appearance of His bundle deflections on termination of the tachycardia, or conversely, disappearance of the His bundle deflection on initiation of the tachycardia, without catheter manipulation; (b) spontaneously occurring or induced supraventricular capture of the His–Purkinje system (with or without ventricular capture) during the tachycardia with the sudden appearance of His bundle deflections; and (c) in the presence of supraventricular capture, H-V intervals comparable to those during sinus rhythm (Figs. 11-6 and 11-7). We have found that the use of more closely spaced bipolar electrodes (l to 5 mm apart) facilitate identification of His bundle activity when it occurs within the ventricular electrogram. Using bipolar recordings
with an interelectrode distance of 5 mm, we have recorded His–Purkinje activity during the tachycardia in approximately 80% of patients.¹⁶

If His deflections are not spontaneously observed during the tachycardia, because of either poor position or obscuration of the His deflection by the ventricular electrogram, rapid atrial pacing can be used to clarify the issue in some cases. If rapid atrial pacing can produce supraventricular capture during the tachycardia—that is, changing the QRS to a sinus QRS—this is diagnostic of VT, regardless of whether the His deflection is seen (proper catheter position) or is not seen (inappropriate catheter position) (Fig. 11-8). Atrial pacing is an active maneuver that may be useful in diagnosing VT even in the absence of recording His bundle electrograms.

(2) The mere presence of the His bundle deflection before the QRS complex with a “normal” H-V interval is not absolutely reliable evidence that the arrhythmia has a supraventricular origin. The “H-V” interval during VT is usually less than that observed during sinus rhythm; hence, if infranodal conduction delay is present during sinus rhythm, the VT may exist in the presence of an apparently “normal” H-V interval (i.e., 35 to 55 msec), but it will be less than the H-V interval during sinus rhythm. Thus, knowledge of A-V conduction during sinus rhythm may be necessary to define what is a “normal” H-V interval during the tachycardia.

The occurrence of an “H-V” (His deflection before the QRS) or a V-H (His deflection after the QRS) interval less than that recorded during sinus rhythm, in the absence of pre-excitation, implies the presence of retrograde activation of the His bundle. It further implies that retrograde conduction time from the “origin” or exit of the tachycardia (as defined by the onset of the QRS) to the His bundle is less than “antegrade” conduction time to depolarize the ventricular myocardium. Some investigators¹⁶,¹⁷ suggest that the site of origin of such a tachycardia is within the His–Purkinje system. These rhythms have generally been referred to as fascicular rhythms,¹⁶,¹⁷ although proof that they originate in the fascicles of the conducting system and differ from other forms of VT is often lacking. As stated earlier, pre-excited tachycardia using either an A-V or nodoventricular bypass tract must be excluded (see Chapter 10).

Two specific circumstances may produce confusing data. The first is a reentrant VT occurring in the setting of a prior infarction. Because ventricular activation (albeit slow enough not to be apparent on the surface ECG) is occurring in diastole, the His–Purkinje system could be activated during this time giving rise to a short V-H or possibly a normal “H-V” interval during the tachycardia. This is schematically shown in Figure 11-9. The time to conduct retrogradely to the His bundle may theoretically be less than the time required to exit from the circuit and produce the onset of the QRS, thereby producing an “H-V” interval. Such tachycardias, which are rare, have “narrow” QRS complexes (Fig. 11-10). It is not rare for a tachycardia to have a V-H interval less than the antegrade H-V interval (Fig. 11-11). In these instances, the tachycardia does not reflect a fascicular tachycardia but reflects engagement of the His–Purkinje system before the onset of the QRS. Retrograde conduction time over the His–Purkinje system is actually much greater than the “V-H” observed during the tachycardia. Depending on the relative conduction time up the His–Purkinje system and through slowly conducting
muscle to give rise to the QRS, the His deflection can occur before, during, or after the QRS.

The second circumstance that can give rise to VT having an H-V interval greater than or equal to the H-V during sinus rhythm is bundle branch reentrant VT.¹⁸,¹⁹ The mechanism, which is the same as isolated bundle branch reentry discussed in Chapter 2, is discussed in more detail in subsequent paragraphs. When bundle branch reentrant VT has an LBBB morphology, retrograde conduction occurs over the left bundle system with antegrade conduction over the right bundle branch. The His deflection typically occurs before the right bundle deflection with an H-V interval approximating the H-V interval during sinus rhythm. The “H-V” interval may be longer than sinus if there is antegrade conduction delay down the RBB. Theoretically, if there is prolonged retrograde conduction over the His–Purkinje system, producing a markedly delayed His deflection (very long V-H), the “in parallel” activation of the His bundle would appear as a “normal” H-V interval. In this case, one must demonstrate that the His deflection is not a requisite for subsequent ventricular activation and thus is not a reflection of bundle branch reentry. Certain criteria are necessary for the diagnosis of bundle branch reentry, all of which provide
some demonstration that retrograde conduction to the His bundle over one bundle branch subsequently leads to antegrade conduction over the contralateral bundle branch to cause the subsequent QRS. Thus, in cases of bundle branch reentry having an LBBB morphology, right ventricular septal activation must precede left ventricular activation. An example of a tachycardia with a His bundle before each QRS that was wrongly considered to be due to bundle branch reentry is shown in Figure 11-12. In this instance, the H-V interval measured to the QRS or to the right ventricular electrogram was greater than 75 msec and exceeded that during sinus rhythm; however, the electrogram recording from the left ventricular apex preceded right ventricular septal activation by 45 msec, therefore excluding bundle branch reentry. For bundle branch reentry with LBBB morphology to occur, the right ventricle must be activated before the left ventricle. The opposite is true for bundle branch reentry with an RBBB pattern. The mechanisms of bundle branch reentry and its variants are discussed in greater detail later in this chapter.

One of the major limitations in evaluating reported results of programmed stimulation to initiate VT is that different protocols have been used in different laboratories. Another limitation is that the reported results of stimulation have included patients with sustained uniform VT, nonsustained VT, and those presenting with cardiac arrest, treated as a single group. Some even report the results in patients who have never had a sustained arrhythmia, but who might be at risk for its occurrence. As mentioned earlier in this chapter, the anatomic and electrophysiologic substrates of these arrhythmias differ.²²,²³,³²,⁸⁹,⁹⁵ It is not surprising that the response to programmed stimulation also differs. Therefore, sensitivity and specificity should only be applied to the use of programmed stimulation for a single arrhythmia type. The only arrhythmia for which such data exist is sustained monomorphic VT.

In addition to the type of arrhythmia and the underlying anatomic substrate, specific features of the methodology of programmed stimulation can influence the ability to initiate the tachycardia. These include the number of extrastimuli, paced cycle length (PCL), site of stimulation, and the current (or voltage and pulse width), and the reproducibility of the response. These parameters are methods used to overcome some general factors that may influence the ability to initiate VT. They include distance from the origin of the arrhythmia, refractoriness at the site of stimulation, and conduction to the potential site of the tachycardia circuit or focus. The lack of control of those variables related to the protocol of programmed stimulation as well as the inclusion of different arrhythmia subtypes and different disease states have led to a marked variability in reported sensitivity, specificity, and reproducibility of programmed stimulation in the study of VT.¹³¹,¹³²,¹³³,¹³⁴,¹³⁵,¹³⁶ This has led to confusion in interpreting results of programmed stimulation and misuse of this technique in the management of arrhythmias. Thus, although some generalities exist regarding the effects of increasing number of extrastimuli, altering drive cycle lengths, and increasing current, the investigator must interpret the response to programmed stimulation in light of the specific arrhythmia being evaluated or whether stimulation is being used for risk stratification postmyocardial infarction.

The appropriate number of extrastimuli used to evaluate programmed stimulation for sustained VT is not universally agreed upon. In general, the greater the number of extrastimuli employed, the increased sensitivity of induction of any arrhythmia; however, this is associated with a decreasing specificity of the technique (Fig. 11-42). The sensitivity of PES to initiate sustained uniform VT increases significantly with the addition of three VES, with little incremental benefit from the addition of a fourth extrastimulus or rapid pacing (Fig. 11-43). Hummel et al.¹³⁷ suggest that if one begins PES with four VES at a short drive– PCL, one can reach an endpoint of inducible monomorphic VT sooner than if one starts with single VES. However, whether or not the VT induced by Hummel’s method is the same as the spontaneous VT was never clarified in their manuscript. The more aggressively one stimulates, the more likely a nonspecific response, usually a polymorphic VT
or VF, can result.¹,³⁸,¹³³,¹³⁸,¹³⁹,¹⁴⁰,¹⁴¹,¹⁴² In general, the induction of VF or very rapid VT requires more VES, delivered at shorter coupling intervals than induction of sustained monomorphic VT. Moreover, the more abnormal the SAECG, the longer the coupling intervals of VES necessary to initiate either VT or VF.¹⁴²

When sustained monomorphic VT is studied, the induction of polymorphic tachycardia must be considered a nonspecific response. Both nonsustained and sustained polymorphic arrhythmias, including VF, can be induced even in normal subjects without a history of VT or cardiac arrest. In our experience, the induction of polymorphic VT and/or VF in normal individuals usually requires multiple extrastimuli delivered at short coupling intervals, usually ≤180 msec (Fig. 11-44). Importantly, the initiating stimulus is associated with marked latency, compatible with local conduction delay at the stimulus site. In these people, these responses have no clinical significance. Thus, in patients without a prior history of sustained ventricular arrhythmias, we try to avoid using coupling intervals <180 msec.

The induction of polymorphic VT and/or VF in a patient who presents with cardiac arrest may have a different implication. By Baysean analysis, this response is more likely to have clinical significance in a patient population in whom similar arrhythmias are present. In other words, because a cardiac arrest may be initiated by a polymorphic tachycardia, the induction of a polymorphic VT in this patient population may be significant (although this is unproven). Despite this, one should always be circumspect when interpreting a polymorphic tachycardia as a clinically significant arrhythmia because, as noted previously, comparable arrhythmias can be induced in patients without any history of arrhythmia.

In contrast, the induction of a hemodynamically tolerated sustained monomorphic tachycardia (particularly with a cycle length ≥240 msec) only occurs in patients with spontaneous VT, cardiac arrest, or in the presence of a substrate known to be arrhythmogenic, such as a left ventricular aneurysm or recent myocardial infarction. It should be noted that the clinical significance of the induction of any arrhythmia,
whether sustained uniform tachycardia or polymorphic tachycardias, in the setting of acute reperfusion or a recent infarction (<2 weeks) remains controversial.²⁵,²⁶ Nonetheless programmed stimulation early after infarction has been useful as a risk stratifier for sudden cardiac arrest.²⁸,¹⁴³,¹⁴⁴,¹⁴⁵,¹⁴⁶,¹⁴⁷ In other situations, induction of monomorphic VT is accepted as indicating that spontaneous occurrence or recurrence is likely and has been used as an indication for device implantation (MUSTT, new Guidelines).

In my opinion, the use of three extrastimuli seems optimal for sensitivity and specificity, for the induction of a clinically seen monomorphic VT due to prior infarction, with the recognition that in occasional patients a sustained monomorphic tachycardia requires four or more extrastimuli for its induction. In such a patient, the risk of additional extrastimuli producing nonspecific arrhythmias versus the benefit of being able to induce and, hence, develop therapy for a clinically relevant monomorphic VT should be considered. This is a reason for using multiple stimulation sites and drive cycle lengths (see below). When cardiac arrest is the presenting syndrome, we would not deliver more than three extrastimuli, because the additional extrastimuli would be more likely to induce polymorphic tachycardias than a uniform one (10:1), which if acted on would lead to the treatment of “nonspecific responses” in some individuals.

It is important that the induced arrhythmia be comparable to the spontaneous arrhythmia to ensure specificity of programmed stimulation. Although this is easily accomplished in the case of sustained monomorphic VT in which documentation of the spontaneous VT by a 12-lead ECG is possible (Fig. 11-45), it is nearly impossible in patients presenting with nonsustained VT or cardiac arrest in whom electrocardiographic documentation of the spontaneous arrhythmia is not available. Moreover, multiple morphologically distinct uniform sustained VT can be induced from the same or different sites (Fig. 11-46). These VT can often be changed back and forth by stimulation during VT (Fig. 11-46), which is particularly common in patients treated with antiarrhythmic agents or early after myocardial infarction. In patients who present with recurrent sustained VT, these tachycardias are relevant. We found that these “additional” uniform VT are commonly responsible for recurrences.¹⁴⁸ In addition to antiarrhythmic drugs, aneurysms are another “risk” factor for spontaneous or inducible multiple VT morphologies. In summary, although the optimal stimulation protocol to ensure maximum sensitivity and specificity for inducing a clinically seen monomorphic VT is not defined, we believe that the number of extrastimuli generally employed should be three. This is based on studies from our laboratory and others¹,⁴²,¹²²,¹⁴⁰,¹⁴¹,¹⁴⁹ that demonstrate that three VES are required to induce sustained monomorphic VT in 20% to 40% of patients presenting with sustained monomorphic VT and in 40% to 60% of patients presenting with cardiac arrest (Fig. 11-47).

It is important that repetition of “critical” coupling intervals or the entire protocol is employed in order to define a true negative study.

Multiple investigators have evaluated whether changing the drive cycle length influences inducibility of VT.¹,⁴²,¹²²,¹³⁷,¹⁴⁹,¹⁵⁰,¹⁵¹,¹⁵²,¹⁵³,¹⁵⁴,¹⁵⁵ Most studies demonstrate that the use of at least two cycle lengths (typically 600 and 400 msec) is required to enhance the sensitivity of induction of sustained uniform VT in patients presenting with that rhythm or sustained VT of any morphology in those presenting with cardiac arrest. Extrastimuli delivered at shorter or longer cycle lengths, or even sinus rhythm, may be necessary to initiate VT in individual patients. Hummel et al.¹³⁷ suggest that if one starts with a PCL of 350 msec, inducibility is achieved more quickly, but whether the induced VT is the same as the spontaneous VT or the protocol was completed was never addressed. Abrupt changes in cycle lengths also may facilitate tachycardia induction.¹⁵¹ In approximately 5% of patients with sustained monomorphic VT (or, less commonly in those presenting with cardiac arrest), VT can be initiated only during sinus rhythm. In 10% to 15%, induction can be accomplished either during sinus rhythm or ventricular pacing.
Thus, most VT that can be induced during sinus rhythm can also be induced during ventricular pacing (Fig. 11-48). In such instances the coupling intervals required to initiate VT tend to be longer during ventricular pacing, but this is unpredictable in individual patients. In the remaining 80% to 85%, extrastimuli delivered during ventricular pacing successfully initiate VT. It is difficult to evaluate whether multiple drive cycle lengths or additional extrastimuli are more important to increasing the sensitivity of induction of VT.¹⁵²,¹⁵³ Both tend to shorten the prematurity with which VES can be delivered.¹⁵¹,¹⁵² The baseline right ventricular effective refractory period does not distinguish between VT requiring single, double, or triple extrastimuli for induction in patients presenting with sustained uniform VT or those with cardiac arrest (Table 11-8).⁴²

The cycle length used can influence the number of extrastimuli required for induction. Theoretically, if one knew the drive cycle length that allows for induction of sustained VT with the least number of extrastimuli, one would use that cycle length, because the incidence of induction of nonspecific arrhythmias would be lower. Unfortunately, one cannot predict which cycle length will facilitate induction of the clinically relevant tachycardia. A standard protocol should include the use of at least two cycle lengths. In our laboratory, we routinely use drive cycle lengths of 600 and 400 msec in all patients as well
as stimulation during sinus rhythm. Additional cycle lengths may be employed if stimulation at these drive cycle lengths fails to initiate tachycardia. The relative success of different cycle lengths on the induction of sustained VT in patients presenting with uniform sustained VT or cardiac arrest is shown in Table 11-9. As noted above, Hummel et al.¹³⁷ suggest that initiating programmed stimulation using four VES delivered at a PCL of 350 msec gives maximum sensitivity. However, this “sensitivity” is just for initiation of any sustained VT, not necessarily the spontaneous VT or other VTs that may be
observed if a complete protocol were performed. Knowledge of all such monomorphic VTs is critical in developing pharmacologic, pacing, implantable defibrillator, or ablative therapy.

Studies have demonstrated that using at least two sites of stimulation enhances the ability to initiate tachycardias.¹,⁴²,¹⁴⁰,¹⁵⁶ In our experience, stimulation from a second site (i.e., other than the right ventricular apex) is needed to initiate sustained VT in patients presenting with sustained uniform VT and, even more importantly, in those with cardiac arrest. If three extrastimuli are delivered only from the right ventricular apex, 10% to 20% of patients will require the use of a second right ventricular or left ventricular site for initiation of sustained (Fig. 11-49). In a study by Doherty et al.,¹⁵⁶ in 58% of patients in whom triple extrastimuli at two cycle lengths failed to initiate a tachycardia from the right ventricular apex, a uniform sustained VT was induced from the right ventricular outflow tract. This accounted for 22% of the total inducible sustained VT. In approximately 60% of patients, the same sustained uniform VT was induced from both the right ventricular apex and right ventricular outflow tract (Fig. 11-50). We previously noted that neither drive cycle length nor ventricular refractory periods at either site was the determinant of mode of induction for patients presenting with sustained VT or cardiac arrest (Tables 11-8 and 11-9).⁴² Thus, the inducibility appears related to the relationship of the wavefront of activation from the site of stimulation and the mechanism at the tachycardia origin. Site specificity for induction would suggest reentry as the underlying mechanism.

Because the number of extrastimuli required to initiate VT may differ depending on site of stimulation, the site that allows use of the lowest number of stimuli is preferred. While nonspecific responses (i.e., polymorphic VT or VF) are often induced with three VES, particularly when delivered at short coupling intervals, only specific responses (e.g., sustained monomorphic VTs) are likely to be induced using fewer stimuli. To determine the influence of stimulation site on the mode of induction and to allow for the safest stimulating protocol to induce the tachycardia (least number of extrastimuli), I recommend alternating stimulation from the right ventricular apex and outflow tract at each specified cycle length and number of extrastimuli. In approximately 20% of patients presenting with sustained uniform VT, a sustained uniform VT will be induced from one site with less stimuli than at another site, thereby preventing the use of a more aggressive stimulation protocol at the other site.¹⁴⁰,¹⁵⁶ If stimulation from the right ventricular apex and outflow tract fails, despite use of multiple drive cycle lengths and up to three extrastimuli, left ventricular stimulation may be employed. The yield is small (2% to 5%) for patients with sustained VT, but because the response of induced sustained VT is relatively specific, it seems worthwhile to use left ventricular stimulation if right ventricular stimulation fails. If only two right VES are used from multiple sites and multiple cycle lengths, left ventricular stimulation may be required in approximately 10%.¹⁵⁷ Induction of sustained uniform VT in patients presenting with cardiac arrest is more likely to require left ventricular stimulation than those presenting with sustained uniform VT (Table 11-10).⁴² The reason for this latter observation is unclear.

Several investigators have evaluated the use of increasing current (5 to 20 mA) in the induction of sustained ventricular
arrhythmias.¹³³,¹⁴⁰,¹⁴¹,¹⁵⁸ All have found an increased incidence of VF when three or more extrastimuli at increased current are used compared to when twice diastolic threshold current is used. In one study, in 60% of patients who were given four extrastimuli at 10 mA, a nonclinical tachycardia (VF, polymorphic VT, nonsustained VT, or uniform VT of different morphology) was induced. Moreover, only a small increment in sensitivity of initiating a uniform sustained tachycardia occurs with increased current. The increased yield of <5%.¹⁵⁸ is far outweighed by the increased incidence of VF; thus, use of currents >5 mA is not recommended for initiation protocols. Even when used, the increased current may either facilitate or inhibit induction of certain tachycardias.¹⁵⁸ The mechanism by which increased current seems to facilitate tachycardia is by shortening the measured local refractoriness; however, the mechanism by which induction is prevented is unknown. This may reflect the lower reproducibility of induction of sustained VT when three extrastimuli are used to initiate a tachycardia. On the other hand, increased current could partially depolarize local tissue, causing slow conduction from the stimulation site such that a critical coupling interval at the VT site is not achieved or that local reentry leading to nonclinical VF is induced (Spear). Although no systematic studies of the effect of pulse width on induction have been conducted, we have observed that pulses >2 msec are associated with an increased incidence of polymorphic tachycardias and VF. Therefore, we recommend use of pulse widths between 1 and 2 msec at twice diastolic threshold as the standard.

The stimulation protocol we recommend for the routine study of patients presenting with sustained uniform VT or cardiac arrest is shown in Table 11-11. We use single VES delivered during sinus rhythm and at PCLs of 600 and 400 msec first from the right ventricular apex and then from the right ventricular outflow tract. If this fails to induce an arrhythmia, we deliver two extrastimuli in the same manner. We then use rapid ventricular pacing. Although this has a relatively low yield of VT induction relative to triple extrastimuli,¹,⁴²,¹²²,¹⁵⁹ it still may induce a uniform tachycardia with a lower incidence of nonspecific responses (i.e., polymorphic VT or VF) than triple extrastimuli. We usually begin rapid pacing at a cycle length of <400 msec and gradually decrease it until 1:1 ventricular capture is lost or a PCL of 200 msec is reached. If this fails to initiate the tachycardia, we employ three VES from both the apex and outflow tract. If these modes of stimulation fail to initiate VT, we repeat the protocol at other basic
cycle lengths. If this fails, we repeat the protocol using other right ventricular or left ventricular sites. In addition, we may use isoproterenol or a Type I agent, such as procainamide, to facilitate induction of the tachycardia. We also perform atrial programmed stimulation and pacing, because occasionally, VT may be induced by these methods or SVT with aberration or pre-excited tachycardias may have been the spontaneous arrhythmia which was misdiagnosed as VT.

Although the use of isoproterenol to facilitate induction of VT has been reported by several investigators,¹⁶⁰,¹⁶¹,¹⁶² in our experience, it has a low yield in patients with postinfarction sustained uniform VT (<5%). In contrast to our experience, Freedman et al.¹⁶¹ suggest that facilitation of VT induction by isoproterenol may be as high as 20%. Isoproterenol is useful in initiation of exercise-induced tachycardias or repetitive monomorphic tachycardia, which are usually nonsustained, that most often originate from the right ventricular outflow tract and are typically based on triggered activity due to DADs. Occasionally epinephrine, atropine, or aminophylline may work alone or in combination to facilitate induction of these rhythms when isoproterenol fails to spontaneously initiate or facilitate initiation by PES. The most common VT due to triggered activity that is clinically encountered arises at the RV outflow tract, but may occasionally arise in the LV outflow tract as well.¹⁶³ Tachycardias due to abnormal automaticity may also be initiated by catecholamines alone. Programmed stimulation cannot reproducibly initiate them, even in the presence of catecholamines.

The use of procainamide or other Type I agents to facilitate induction of a tachycardia is not as well recognized. Facilitation of induction of sustained VT is not uncommon in patients with coronary artery disease and prior infarction (with or without angina) in whom no arrhythmia or, more often, a nonsustained tachycardia (uniform or polymorphic) is induced in the baseline state, particularly if the clinical tachycardia, either sustained monomorphic VT or a cardiac arrest, occurred following drug administration (Fig. 11-51). Once monomorphic tachycardia is induced in such patients,
it behaves just as the other reentrant monomorphic tachycardias described later in this chapter. This is one of the observations that link the underlying mechanism of the previously mentioned arrhythmias to that of sustained uniform VT.

The response to programmed stimulation that is obviously most difficult to interpret is the induction of polymorphic VT in a patient who has experienced a cardiac arrest. As stated earlier, aggressive stimulation (e.g., triple extrastimuli) can induce similar arrhythmias in patients who have never had a cardiac arrest, or even in people with normal hearts. In such instances, the induction of polymorphic VT is a nonspecific response and lacks relevance. Therefore, we believe that the end point of programmed stimulation should be induction of the clinical arrhythmia or, in this instance, the assumed ventricular arrhythmia. In the case of patients presenting with a cardiac arrest, although doubt will always exist, I believe one must treat the reproducible induction of a polymorphic arrhythmia as a possible indicator of the clinical arrhythmia. It cannot, however, in and of itself help one to understand the mechanism of cardiac arrest, although some investigators have used the induction of polymorphic VT to guide therapy (see Chapter 12). Features that suggest a polymorphic VT may be mechanistically meaningful are (a) reproducible initiation of the same polymorphic template, particularly from different sites, and (b) the transformation of the polymorphic VT to a monomorphic VT by procainamide.¹⁶⁴,¹⁶⁵

Conduction delay is required for the initiation of reentrant rhythms (see following discussion). Therefore, an inverse relationship between the coupling interval of the extrastimulus initiating the tachycardia and the interval from the stimulus to the first complex of the tachycardia favors reentry. Similarly, an inverse relationship between the drive cycle length during which extrastimuli at the same coupling interval initiate the tachycardia, and the interval to the onset of the tachycardia, would also favor reentry. When multiple VES are used, it is difficult to evaluate this relationship. In either case, if a reentrant rhythm is present, the initial cycle length would reflect conduction through the tachycardia circuit, which, in the absence of exit block, should demonstrate the same or longer cycle length as the remaining tachycardia cycles, depending on whether any conduction delay is produced in the circuit on initiation.

These findings are in contrast to those observed in triggered rhythms due to DADs in ventricular tissue that often exhibit a direct relationship to the PCL or to the coupling intervals of the extrastimuli that initiate them. Typically, in tachycardias due to DADs the initial cycle of the tachycardia usually bears a direct relationship to the PCL, with or without a direct relationship to the coupling interval of extrastimuli delivered.¹⁸⁰ Thus, the shorter the PCL, with or without
extrastimuli, that initiates the tachycardia, the shorter the interval to the first beat of the tachycardia and the shorter the initial cycle length of the tachycardia. Occasionally, with early extrastimuli in digitalis-intoxicated preparations, a jump in the interval to the onset of the triggered rhythm occurs such that it is approximately double the interval to the onset of the tachycardia initiated by later coupled extrastimuli. This has been explained by failure of the initial DAD to reach threshold while the second reaches threshold. Thus, in triggered activity due to DADs in ventricular tissue, the coupling interval of the initial complex of the tachycardia either shortens or suddenly increases in response to progressively premature extrastimuli. It never demonstrates an inverse or gradually increasing relationship. It must be reiterated that, in response to drive cycle length, the onset of the tachycardia always has a direct relationship with the drive cycle length, regardless of the tissue used. Only with the addition of very early extrastimuli or occasionally very rapid pacing (<300 msec), the sudden jump in the interval to the first complex of the tachycardia may be observed. We have never noted a direct relationship between PCL and the interval to the onset of the tachycardia or early tachycardia cycles in the case of paroxysmal, nonexercise-related, sustained monomorphic VT in humans with structural heart disease.

When single extrastimuli are delivered, and one can assess the relationship between coupling interval and the interval to the first VT complex, one sees an inverse relationship in approximately 40% of patients (Figs. 11-71 and 11-72).¹,¹²²,¹⁹³,¹⁹⁴,¹⁹⁵ Sometimes one initially sees an isolated repetitive response followed by initiation of the tachycardia (Fig. 11-71), while at other times, the first extrastimulus initiates a sustained VT (Fig. 11-72). When the drive cycle length is short and tachycardia can be initiated by extrastimuli delivered at the same coupling interval, an inverse relationship is also seen (Fig. 11-73). Most often, particularly when multiple extrastimuli and/or rapid pacing initiate a tachycardia, there is no direct relationship or measurable relationship to the onset of the tachycardia or tachycardia cycle length (Fig. 11-66). In many patients, the coupling interval to the first complex of the tachycardia as well as the initial tachycardia cycle length are unaffected by the mode of stimulation. Thus, as shown in Figure 11-74, atrial pacing at a cycle length of 320 msec, ventricular pacing at 360 msec, and a single extrastimulus delivered at a PCL of 400 msec initiate VT with identical intervals to the onset of the tachycardia and initial cycle lengths


of the tachycardia. We have never seen a direct relationship of PCLs to onset intervals of tachycardias in patients with sustained uniform VT associated with coronary artery disease. Although we have not studied tachycardias associated with digitalis intoxication, Gorgels et al.¹⁹⁶ demonstrated a direct relationship of such rhythms in experimental canine models of digitalis intoxication. Whether a human VT associated with digitalis intoxication behaves the same way has not yet been evaluated. When multiple VES and/or rapid pacing are used to initiate the tachycardia, no consistent relationship has been observed between the initiating sequence (number and coupling interval of extrastimuli, paced drive cycle lengths, or cycle lengths of burst pacing) and the initial characteristics of the tachycardia (the interval to the onset of the tachycardia or early tachycardia cycle length).

With triggered rhythms, the site of stimulation should have no effect on initiating a tachycardia as long as the impulse reaches the site of triggered activity. This is not so for reentrant arrhythmias, where wavefront of activation may be important in developing block and slow conduction. Unpublished observations from our laboratory have shown that single and double extrastimuli delivered at PCLs of 600 or 400 msec always reach the “site of origin” of left VTs, even in the presence of markedly abnormal conduction manifested by abnormal electrograms. One can usually demonstrate changes in local abnormal electrograms at arrhythmogenic sites in response to different sites of stimulation. This observation supports the role of tissue anisotropy in creating conduction delays and/or block associated with initiation of VT. Thus, failure to reach the site of tachycardia origin cannot be used to explain differences in incidence of inducibility by the site of stimulation. As stated earlier, although in most patients, the same tachycardia can be initiated from both the right ventricular outflow tract and right ventricular apex (Figs. 11-50 and 11-62), this is most often true when single extrastimuli (Fig. 11-75) initiate the tachycardia. The site of stimulation may be an extremely important factor in initiating VT in humans if only the right ventricular apex is used. Twenty to 30% of patients will require stimulation from a second right ventricular site if two extrastimuli delivered at two PCLs are employed. If three extrastimuli are employed, 10% to 25% of patients will require a second right ventricular site.¹⁴⁰,¹⁵⁶ As noted earlier, we have found that if three extrastimuli fail to initiate sustained uniform VT from the right ventricular apex, 22% of tachycardias can be initiated from the right ventricular outflow tract (Fig. 11-76).¹⁵⁶ If only two extrastimuli are involved, nearly 10% of patients will require stimulation from the left ventricle (Fig. 11-77).¹⁵⁷ If a protocol including three extrastimuli delivered at two right ventricular sites and at multiple drive cycle lengths is used, the incidence for requirement of left ventricular stimulation to initiate a sustained VT is <5% (Fig. 11-78).¹,⁴²,¹²²,¹⁴⁹

Because the incidence of inducing nonspecific polymorphic tachycardias increases with the use of increasing numbers of extrastimuli, one should employ a protocol that allows testing from multiple sites with the least number of stimuli before using more aggressive protocols. Using the protocol shown in Table 11-11, we have found that in approximately 20% of people sustained monomorphic VT can be initiated with less extrastimuli at one site than at another. This is an important observation, if one wants to limit the potential for developing polymorphic VT and VF. A dramatic example is shown in Figure 11-79 in which triple extrastimuli from the right ventricular apex could initiate only a polymorphic VT in a patient with spontaneous sustained monomorphic VT. Stimulation from the right ventricular outflow tract at longer coupling intervals induced two different sustained monomorphic VTs, which were identical to those spontaneously occurring in the
patient. An even more dramatic example of the influence of inducibility is shown in Figure 11-80. Here, triple extrastimuli from the right ventricular apex failed to initiate any VT, but a single extrastimulus delivered from the right ventricular outflow tract initiated a well-tolerated sustained monomorphic VT. Thus, a second right or left ventricular site may be required for initiation or may make initiation possible with a fewer number of stimuli in 30% to 40% of patients. As noted earlier, patients with sustained uniform VT who present with a cardiac arrest more frequently require left ventricular stimulation than patients presenting with tolerated uniform VT.⁴² The reasons for this are unclear, but may be related to a lesser amount of conduction abnormalities and/or greater extent of homogeneous refractoriness produced by a broad wavefront from the RV compared to that produced by a more narrow wavefront initiated in the LV. In sum, the demonstration of absolute or relative site specificity for initiation of VT, using standard stimulation protocols that have been demonstrated to reach the site of tachycardia origin, favors a reentrant mechanism for VT. Rhythms related to DADs should show no evidence of site specificity as long as comparable coupling intervals can reach the site of DADs.

Rhythms that are due to automaticity or triggered activity do not require associated conduction delay and/or block for initiation while classically, reentry requires conduction delay with or without the development of block, which may be present at baseline. As discussed earlier, evidence of conduction abnormalities is virtually universal in patients with cardiac disease (primarily coronary artery disease) during sinus rhythm, manifested by abnormal electrograms during endocardial mapping (see earlier discussion on Substrate), or positive SAECGs, in patients in whom inducible tachycardias are present. Theoretically, if reentry was the mechanism of the tachycardia, electrical activity should occur throughout the tachycardia cycle. Thus, during diastole, conduction must be extremely slow and in a small enough area such that it is not recorded on the surface ECG. The demonstration that initiation of the tachycardia depended on a critical degree of slow conduction, manifested by fragmented electrograms spanning diastole, and that maintenance of the tachycardia was associated with repetitive continuous activity, would be compatible with reentry.¹⁹⁷ The initiation of tachycardias associated with continuous activity was initially recorded in acute ischemic arrhythmias in an experimental canine model by Boineau and Cox¹⁹⁸ and Waldo and Kaiser¹⁹⁹ and subsequently by El-Sherif et al.²⁰⁰ in a canine model of infarction with inducible sustained VT. We have found similar, continuous repetitive activity in local areas of the endocardium, which was required to initiate and maintain the tachycardia in humans in 5% of patients during catheter mapping¹⁹⁷ and in 10% of patients using intraoperative mapping. Although some have questioned continuous activity as potentially being due to motion artifact,⁴⁴,²⁰¹,²⁰² in vitro tissue studies⁴³,⁴⁴ have shown that such fragmented electrograms are not due to motion artifact. In humans, Waxman and Sung²⁰³ and Brugada et al.²⁰⁴ claimed that continuous activity is not related to the tachycardia mechanism, but the examples that they proposed demonstrating continuous activity showed inconsistent electrograms lasting only two cardiac cycles. This clearly would not meet our definition of continuous activity, which is required to maintain the tachycardia. Electrical signals that come and go throughout diastole should not be considered continuous.

This is not to say that all fragmented electrical activity noted at the onset and during VT represents reentrant activity. Such activity may represent artifacts, dead-end pathways, or electrical activity otherwise unrelated to the genesis and maintenance of the tachycardia. For continuous activity to be consistent with reentry, the following must be demonstrated: (a) The initiation of VT depends on broadening of electrograms that span diastole, as in Figures 11-81 and 11-82. (b) The tachycardia maintenance depends on continuous activity, such that termination of the continuous activity, either spontaneously or following stimulation, without affecting the tachycardia would exclude such “continuous” activity as requisite for sustaining the tachycardia (Figs. 11-83 and 11-84). (c) Pacing at a cycle length comparable to VT does not produce a broadening of electrogram to span the cardiac cycle and appear continuous, that is, create an electrogram whose duration equals the PCL. (d) Motion artifact is excluded (this is easiest because such electrograms are recorded only in infarcted ventricle, and never from moving contractile normal ventricle. (e) The continuous activity is recorded from a circumscribed area (Figs. 11-81 to 11-84). (f) Finally, if possible, ablation of the area from which continuous activity is recorded will terminate the tachycardia. Thus, the mere presence of “continuous activity” at the onset and during VT does not automatically imply that this electrical activity is related to the genesis and maintenance of the tachycardia. One must stimulate during VT to prove that the presence of such electrical activity is requisite for the arrhythmia. Persistent changes in the repetitive continuous waveform produced by stimulation should be associated either with termination of the arrhythmia or with changing it to a different tachycardia. A change in the electrogram on the stimulated beat may reflect antidromic capture by the stimulated wavefront of part of the tissue from which the continuous activity is recorded. The tachycardia would either be reset or terminated if the electrical signals were recorded from the reentrant circuit (see subsequent discussion on Resetting and Entrainment).

Conduction delay that is not quite continuous can also be seen at initiation of tachycardia in an additional 5% of patients (Fig. 11-85). Conduction delays producing nearly continuous activity may critically depend on rate. They may only be seen when extrastimuli are delivered during a short-paced drive cycle length (Fig. 11-85) or during a burst of ventricular pacing (Fig. 11-86). If the recording electrode is not recording the entire circuit, one may see broadening of the electrogram such that the delayed late component becomes the early component during the tachycardia (Figs. 11-86 and 11-87). Proof that this late potential in fact becomes an early potential (as far as the tachycardia circuit is concerned) requires demonstration that this potential bears a fixed relationship to the subsequent QRS despite changes in cycle length observed spontaneously or during pacing. This is discussed further in the section regarding methods of localizing VT. It is imperative that such validation be attempted so that dead-end pathways, which are late and unrelated to the tachycardia, are not mistaken for early activity. Failure to demonstrate continuous activity in all cases suggests that the tachycardia circuit is larger than the recording area of the catheter and/or that the catheter is not covering the entire circuit. Because catheter and intraoperative mapping of VT associated with prior infarction suggests that most tachycardias exit a diastolic pathway 1 to 3 cm long and a few millimeters to 1 cm wide, with a circuit area probably in excess of 4 cm², failure to record continuous activity is not surprising (see later section on activation mapping during VT). Continuous activity, when observed, is always found at sites that demonstrate a markedly abnormal electrogram in sinus rhythm (Fig. 11-88; also see Figs. 11-81 to 11-84). Evidence supporting the significance of fractionated electrograms and continuous activity has been reviewed by Josephson and Wit.⁴³

Since the recognition of reentry within the His–Purkinje system as a normal phenomenon that can produce isolated repetitive responses, several investigators have observed persistent His–Purkinje reentry try as a form of macroreentrant VT.¹⁸,¹⁹,²⁰⁵ The demonstration of a macroreentrant circuit using the bundle branches, or more recently the fascicles,²⁰⁶ is of more than intellectual interest because this type of tachycardia can be cured by catheter ablation techniques.²⁰⁵,²⁰⁶,²⁰⁷,²⁰⁸ Sustained bundle branch reentrant VT is uncommon. Although Casceres et al.¹⁹ suggested that it is responsible for 6% of VT, I have observed only 14 instances in which bundle branch reentry was the sole inducible, and presumed clinical, monomorphic VT out of approximately 1650 consecutively studied
cases. None of our 14 cases had a prior infarction: 10 had cardiomyopathy, 2 had aortic valve disease, and 2 had myotonic dystrophy. All but 2 of our patients and the vast majority reported in the literature¹⁸,¹⁹,²⁰⁵,²⁰⁶,²⁰⁷ had either complete or incomplete LBBB pattern and H-V intervals ≥65 msec in sinus rhythm. They all had bundle branch reentry with an LBBB pattern (see Chapter 2; Fig. 11-89). Two patients had incomplete RBBB, and had bundle branch reentry with a RBBB pattern. In contrast, in patients with prior infarction (virtually always a large anterior infarction complicated by bifascicular block) interfascicular reentry (using anterior and posterior fascicle) is the only macroreentrant rhythm observed requiring the His–Purkinje system (see Chapter 2). Moreover, I have never seen interfascicular reentry as the sole arrhythmia in these patients; they invariably have multiple intramyocardial VTs as well. I have never seen bundle branch reentry using the right and left bundle branches in this patient population. This is consistent with our observation that when RBBB occurs and persists following anteroseptal infarction, complete bidirectional RBBB is present. Interfascicular reentry may also be seen in
patients without infarction, including patients with bifascicular block due to degenerative disease of the conducting system. I have seen 2 patients with both BBR with an LBBB pattern and interfascicular reentry. During their BBR a changing axis was observed. In both cases, interfascicular reentry occurred after ablation of the RBB (Fig. 11-90A–C). Our failure to observe a higher incidence of sustained bundle branch reentry may be directly related to the patient population studied and, to a lesser degree, to the stimulation protocol used. We have studied only 112 patients with sustained uniform VT and cardiomyopathy, only 8 of whom had bundle branch reentry as their only arrhythmia and an additional 2 had BBR and interfascicular reentry. I have seen another seven patients in whom multiple VTs accompanied bundle branch reentry. Although Casceres et al.¹⁹ suggest, and I agree, that this disorder is often unrecognized, I think the patient population is the most important factor in trying to determine the frequency of its occurrence. Stimulation is generally performed from the right ventricle, which is much less likely to give rise to bundle branch reentry with an RBBB pattern, although we have seen such a patient (see below). Moreover, as noted above the majority of patients with bundle branch reentry and interfascicular reentry have spontaneous and/or inducible intramyocardial reentrant VT as well.

To prove bundle branch reentry is operative, several criteria should be met: (a) critical degree of retrograde His–Purkinje conduction delay (V-H prolongation) for initiation; (b) an H-V interval during the tachycardia ≥H-V during sinus rhythm can be seen if the His bundle is recorded distally. It is also possible to see a shorter H-V interval during the tachycardia than sinus rhythm if a very proximal His bundle (far from the turnaround site) is recorded; (c) during bundle branch reentry with an LBBB pattern, the His deflection occurs before the right bundle deflection (the H-RB during VT can be greater or less than the H-RB in sinus rhythm, depending on the recording site of the His bundle relative to the turnaround site). The RB to V should be greater than or equal to the R-B to V during sinus rhythm. During bundle branch reentry with an RBBB pattern the RB potential will occur before the His potential which will in turn precede the LB potential; (d) changes in H-H interval during the tachycardia precede changes in the V-V interval; (e) an atrial premature depolarization that blocks below the His bundle deflection should stop bundle branch reentry; (f) bundle branch reentrant VT can be prevented by simultaneous right and left ventricular stimulation; and (g) ablation of the right or left bundle branch could cure the arrhythmia.

A typical example of bundle branch reentrant tachycardia with an LBBB pattern is shown in Figure 11-89. In this case—a patient with myotonic dystrophy—incomplete LBBB is present during sinus rhythm with a markedly prolonged H-V interval of 112 msec and an H-RB of 56 msec. During the tachycardia, the classic sequence of V-H-RB is noted, with the H-V slightly greater than that observed during sinus rhythm. However, as stated above the H-V and H-RB may be less than sinus rhythm if the His bundle deflection is recorded very proximally. The H-V during the tachycardia would then
represent the difference between retrograde conduction to the proximal His bundle and antegrade conduction to the right bundle. I have not seen an H-V in VT more than 15 msec shorter than sinus in either a single bundle branch reentrant complex or sustained bundle branch reentry. A much shorter H-V during tachycardia than sinus rhythm is the rule in interfascicular reentry (see below).

Unfortunately, right and/or left bundle branch potentials are not always recorded so that the typical activation sequences (LB-H-RB-V or RB-H-LB-V) are not available for analysis. As noted earlier in the chapter, even if either sequence is present, the His–Purkinje system (usually, the left bundle branch) could be activated passively in the retrograde fashion to produce a His-RB-V sequence during a tachycardia with an LBBB pattern without reentry requiring the bundle branches. This was pointed out earlier in the chapter, in Figure 11-12, in which a wide-complex tachycardia with left bundle and left axis deviation was induced by ventricular stimulation and V-H prolongation, with an H-V interval during the tachycardia greater than that during sinus rhythm. This tachycardia, although meeting initiation criteria and H-V interval criteria, was not due to bundle branch reentry because left ventricular mapping demonstrated earliest activity at the apex of the left ventricle. For documentation of bundle branch reentry using the right bundle branch antegradely and the left bundle branch retrogradely, right ventricular excitation must precede the left ventricular excitation. If left ventricular mapping cannot be done, other critical and essential elements for the diagnosis of bundle branch reentry must be tested. The most important of these is the demonstration that changes in the H-H and RB-RB and/or LB-LB interval during the tachycardia precede changes in the V-V interval. These changes can be initiated by ventricular stimulation during the tachycardia or may occur spontaneously following initiation. This observation, shown in Figure 11-91, is essential in proving that a macroreentrant circuit using the proximal His–Purkinje system is operative. Casceres et al.¹⁹ have shown this elegantly by linear regression analysis (Fig. 11-92). As stated earlier, the vast majority of bundle branch reentrant tachycardias have had LBBB morphology and have used the left bundle conducting system retrogradely and the right bundle branch system antegradely. Although the reverse situation—an RBBB reentrant tachycardia (using left bundle system antegradely and right bundle branch system retrogradely)—has been reported, the same criteria used for typical bundle branch reentry are more difficult to document without obtaining an LB recording. Although the RB-H-V sequence may be noted, this may be a passive phenomenon. Tachycardia oscillations with V-V intervals dependent on prior RB-H intervals should be looked for, but are difficult to see because the RB is usually activated during the QRS. Thus, an LB potential is mandatory to confirm the diagnosis. It is of interest that of the cases reported to be bundle branch reentry with an RBBB pattern, an incomplete RBBB with a long H-V was seen during sinus rhythm. This was the case in one of the two right bundle branch reentrant VT I have seen (Figs. 11-93 and 11-94).

Why is bundle branch reentrant VT as rare as an isolated form of VT if single bundle branch reentrant complexes can be seen in 50% of normal patients?¹⁸,²⁰⁵,²⁰⁹ The reason lies in the underlying substrate of conduction delay in the left or right bundle branch system. True complete bundle branch block of either type would make bundle branch reentry impossible. Therefore, conduction delay, manifested by H-V prolongation, but not true block must be present in both the left and right bundle systems for typical bundle branch reentry to occur. Although the mode of induction of bundle branch reentry usually is by single extrastimuli, Casceres et al.¹⁹ have reported that sudden short-to-long change in cycle length before the introduction of extrastimuli facilitates induction of bundle branch reentry. This is related to the previously demonstrated effect of altered cycle length on His–Purkinje refractoriness.¹⁵¹

Bundle branch reentry not infrequently is observed at the initiation of monomorphic intramyocardial VT but is not necessary either to initiate or maintain the tachycardia. This can be proven by the demonstration that the tachycardia can be initiated with or without bundle branch reentry
(Fig. 11-95) and the failure to demonstrate His deflections with a normal or greater than normal H-V interval or a dependence of VT cycle length on prior H-H intervals.

Because His bundle deflections may be observed in approximately 80% of VTs,¹⁶ does this imply that the fascicles are an integral component of the tachycardia circuit? I believe that in patients who have diseased hearts incorporation of a fascicle in the tachycardia circuit is not necessary to explain the presence of a His deflection before or just following the onset of the QRS. The lack of requirement for the more proximal His–Purkinje system has been demonstrated by intermittent His deflections (Fig. 11-96). These are typically in a 2:1 fashion but may also be seen in a 3:2 pattern or, less commonly, in a Wenckebach periodicity (Fig. 11-97). In patients with chronic coronary disease, the relative timing of the retrograde His deflection in the QRS depends on how

quickly the His–Purkinje system is engaged and how slowly the impulse reaches the ventricular myocardium to begin to produce the QRS. Thus, retrograde His potentials can actually precede the QRS or follow it. The retrograde His deflection appears to reflect passive activation of the His–Purkinje system and not involvement of the His–Purkinje system in the reentrant circuit. The bases for this conclusion are threefold: (a) His–Purkinje deflections may appear intermittently, as noted. (b) The changing V-H interval can occur without a change in cycle length (Fig. 11-98). If the His–Purkinje system were involved, a change in V-H interval should be mirrored by a change in tachycardia cycle length. (c) Marked changes in tachycardia cycle length can be present with no change in V-H interval (Fig. 11-99). These data suggest two things. First, the His–Purkinje system is passively activated in VT associated with coronary artery disease and is not related to the reentrant circuit per se. Second, engagement of the His–Purkinje system allows for more rapid activation of the myocardium, which in turn results in a narrower QRS. Our data analyzing the relationship between the V-H interval and QRS duration in VTs of similar morphology in the same patient demonstrate a direct relationship between the V-H interval and the QRS (Fig. 11-100).¹⁶ Thus, the His–Purkinje system is important for global ventricular activation, but at least the more
proximal areas do not seem to participate in the tachycardia mechanism. Whether the same is true in patients with normal ventricles and sustained VT has not been evaluated.

VT due to interfascicular reentry, in contrast to bundle branch reentry, is most commonly seen in patients with coronary artery disease, specifically those with an anterior infarction and either left anterior or posterior hemiblock. A schema is shown in Figure 11-101. In these patients RBBB is complete and bidirectional, so true bundle branch reentry cannot take place. In such cases there is slow conduction in the “apparently blocked” fascicle. Initiation of interfascicular reentry occurs when an APD, increase in heart rate, or a VPD produces transient block in the slowly conducting fascicle. The impulse conducts over the “healthy” fascicle, giving rise to a QRS identical to that in sinus rhythm, and then reenters the blocked fascicle to induce reentrant VT. In this instance the H-V interval will always be >40 msec shorter than the H-V in sinus rhythm, and the LB potential will precede the His potential (Figs. 11-90 and 11-102). When interfascicular reentry occurs in the setting of an anterior infarction, “cure” by
ablation is not possible because other myocardial VTs are, in my experience, always present and the ejection fractions are usually below 30%, thereby mandating a defibrillator to improve survival. This is not the case in the occasional patient with interfascicular reentry in the setting of degenerative conducting system disease with preserved ventricular function. In such a patient cure of the VT is possible by ablation of the diseased fascicle, although a pacemaker would likely be required.