Atrioventricular Conduction System Disease

Anatomy of the His Bundle

The AV nodal tissue merges with the His bundle, which runs through the inferior portion of the membranous interventricular septum, and then in most cases, continues along the left side of the crest of the muscular interventricular septum. As shown in Figure 14-3 , the proximal part of the His bundle rests on the right atrial-left ventricular (RA-LV) part of the membranous septum and the more distal part travels along the right ventricle-left ventricular (RV-LV) part of the membranous septum immediately below the aortic root. Recent macroscopic anatomic investigation revealed three distinct locational variations of the His bundle relative to the membranous part of the ventricular septum. In type I (46.7% of 105 cases), the His bundle consistently coursed along the lower border of the membranous part of the interventricular septum but was covered with a thin layer of myocardial fibers spanning from the muscular part of the septum ( Fig. 14-4 ). In type II (32.4%), the His bundle was apart from the lower border of the membranous part of the interventricular septum and ran within the interventricular muscle ( Fig. 14-5 ). In type III (21%), the His bundle was immediately beneath the endocardium and coursed onto the membranous part of the interventricular septum (naked AV bundle) ( Fig. 14-6 ). These anatomic variations of the His bundle may have clinical implications for permanent His bundle pacing and to avoid His bundle injury during surgical reconstruction of the membranous part of a ventricular septal defect. The His bundle usually receives a dual blood supply from both the AV nodal artery and branches of the LAD. Unlike the SA and AV nodes, the bundle of His and Purkinje system have relatively little autonomic innervation.

The right bundle branch (RBB) originates from the His bundle. It is a narrow structure that crosses to the right side of the interventricular septum and extends along the right ventricular (RV) endocardial surface to the region of the anterolateral papillary muscle of the right ventricle, where it divides to supply the papillary muscle, the parietal RV surface, and the lower part of the RV surface ( Fig. 14-7 ). The proximal portion of the RBB is supplied by branches from the AV nodal artery or the LAD artery, whereas the more distal portion is supplied mainly by branches of the LAD artery.

The left bundle branch (LBB) is anatomically much less discrete than the RBB. The LBB may divide immediately as it originates from the bundle of His or may continue for 1 to 2 cm as a broad band before dividing. The LBB fibers spread out over the left ventricle in a fan-like manner, a “cascading waterfall,” with many subendocardial interconnections that resemble a syncytium rather than two anatomically discrete distinct branches or fascicles.

As originally proposed by Rosenbaum, however, it is clinically useful to consider the LBB as dividing into an anterior branch or fascicle and a larger and broader posterior branch or fascicle, both of which radiate toward the anterior and posterior papillary muscles of the left ventricle respectively. The LBB and its anterior fascicle have a blood supply similar to that of the proximal portion of the RBB; the left posterior fascicle is supplied by branches of the AV nodal artery, the posterior descending artery, and the circumflex coronary artery.

Electrocardiography

First-degree AV block usually is caused by conduction delay within the AV node. Much less frequently, first-degree AV block is caused by intra-atrial or infra-Hisian conduction delay. Localization of the site of second-degree AV block to the AV node or His-Purkinje system can be obtained by His bundle recording during invasive electrophysiologic testing, but in most cases, careful analysis of the electrocardiogram (ECG) and the effect of various pharmacologic agents on the block will suffice. Adherence to precise definitions of second-degree AV block, particularly in cases of 2 : 1 AV block and suspected type II AV block, is critical to avoiding diagnostic errors that could result in potentially unnecessary permanent pacemaker implantation. Furthermore, type I and type II designations refer only to ECG patterns and not to the anatomic site of block.

Classic type I (Wenckebach) second-degree AV block has three characteristics: (1) progressive P-R interval prolongation before the nonconducted beat, (2) progressive decrease in the increment of P-R interval prolongation, and (3) progressive decrease in the R-R interval parallel to the progressive decrease in the increment of change in the P-R interval. All patterns of type I second-degree AV block not having this pattern are called “atypical” patterns, although in actuality they may occur more often than the classic variety ( Fig. 14-8 ).

As a general rule, type I second-degree AV block with a narrow QRS complex is almost always caused by delay within the AV node. Delay within the His bundle (intra-Hisian block), however, is a rare cause of type I second-degree AV block with a narrow QRS and requires an electrophysiologic study for definitive diagnosis. Intra-Hisian block should be suspected in a patient with a narrow QRS if type I second-degree AV block is provoked by exercise. In contrast, type I AV nodal block at rest improves with exercise. When type I second-degree AV block is associated with concomitant bundle branch block (BBB), the site of delay or block is in the His-Purkinje system (infranodal) in up to 60% to 70% of cases.

Type II second-degree AV block is defined as a single nonconducted sinus P wave associated with fixed P-R intervals before and after the blocked beat ( Fig. 14-9 ). The sinus rate must be stable (i.e., constant P-P intervals), and there must be at least two consecutive conducted P waves to determine the P-R interval, which can be either normal or prolonged. Type II second-degree AV block should not be diagnosed in the case of a nonconducted atrial premature beat or if there is simultaneous sinus slowing and AV nodal block (e.g., hypervagotonia). Type I block with relatively long Wenckebach sequences and small increases in AV nodal conduction time may be confused with type II AV block but should not be classified as such (even though the site of block may be either AV nodal or infranodal in such cases). Type II second-degree AV block is most often encountered when the QRS complex is prolonged (in about 70% of cases) and is localized within the His-Purkinje system; in contrast, type II AV block with a narrow QRS is within the His bundle (i.e., intra-Hisian). Sudden AV block of more than one impulse with stable sinus rhythm and 1 : 1 AV conduction with constant P-R and P-P intervals before and after the block has been labeled “advanced AV block,” “paroxysmal AV block,” and “type II AV block.” Although this rhythm does not conform to the strict definition of type II block (i.e., a single blocked beat), it does suggest that the anatomic site of AV block is infranodal, and that permanent pacing is indicated. On the other hand, Wenckebach periodicity before the development of high-grade AV block suggests an AV nodal site.

Lange et al reported on their experience with a large number of patients with transient second-degree AV block and narrow QRS complexes detected on ambulatory Holter monitoring. The researchers emphasized the many ways in which second-degree AV block can be manifested. Classic type I AV block, with progressive PR prolongation to more than 40 msec during at least three beats before the blocked P waves, was seen in only 50% of patients. Another pattern observed was a subtler Wenckebach periodicity with minor PR prolongation of 20 to 40 msec before a blocked P wave in 29% of patients. A third pattern, seen in 8% of patients and termed pseudo-Mobitz type II AV block, demonstrated nearly constant P-R intervals before the blocked P wave, followed by PR shortening on the subsequent conducted beat (see Fig. 14-8 ). Classic Mobitz type II second-degree AV block, with constant P-R intervals for at least three beats before the blocked P wave, followed by the same P-R interval after the blocked P wave, was seen in 4% of patients (see Fig. 14-9 ). A mixed, type I Wenckebach and pseudo-Mobitz type II AV block was seen in 6% of all patients. Of patients showing periods of pseudo-Mobitz type II block, 44% also demonstrated classic Wenckebach conduction patterns at some time. Slowing of the sinus cycle length often preceded the blocked P wave in both classic and pseudo-Mobitz type II AV blocks ( Fig. 14-10 ).

Diagnosis of the site of AV block may be problematic with 2 : 1 atrioventricular block, which should not be classified as type I or type II block. The anatomic site in 2 : 1 AV block can be in the AV node or His-Purkinje system ( Fig. 14-11 ). The most likely site of AV block can often be determined by noting the company that the 2 : 1 AV block keeps. When 2 : 1 AV block is associated with a wide QRS complex, the block is in the His-Purkinje system in 80% and the AV node in 20% of cases ( Fig. 14-12 ). A long P-R interval (>0.30 second) on conducted beats during 2 : 1 AV block with a narrow QRS complex suggests an AV nodal site, whereas a normal P-R interval favors intra-Hisian block.

In general, the response of the block, particularly 2 : 1 AV block, to pharmacologic agents may help to determine the site. Atropine generally improves AV conduction in patients with AV nodal block; however, atropine is expected to worsen conduction in patients with block localized to the His-Purkinje system because of its effect on increasing sinus rates without improving His-Purkinje conduction ( Fig. 14-13 ). Carotid sinus stimulation is expected to worsen block localized to the AV node, whereas it either has no effect or improves conduction in patients with His-Purkinje system disease by causing sinus node slowing. However, the effect of any given drug may be difficult to predict because its effect on the sinus node may be greater than its effect on the AV node. For example, atropine may improve AV node conduction, but if atropine causes excessive SA node acceleration, AV conduction may improve marginally, or not at all. The response to an infusion of isoproterenol is less clear. Isoproterenol may improve conduction disorders localized in the AV node and occasionally in the His-Purkinje system.

The diagnosis of complete heart block (CHB) rests on demonstration of complete dissociation between atrial and ventricular activation. Care must be taken to distinguish transient AV dissociation, caused by competing atrial and junctional or ventricular rhythms, with similar rates (so-called isorhythmic AV dissociation). If sufficiently long monitoring strips are available, intermittent conduction of appropriately timed atrial events is seen. Temporary atrial pacing can be performed to accelerate the atrial rate to overdrive the competing junctional or ventricular arrhythmia, demonstrating intact AV conduction. In the presence of atrial fibrillation (AF), CHB can be inferred when the ventricular rate becomes regular rather than the typical, irregular ventricular response ( Fig. 14-14 ). Digoxin toxicity may be the cause of heart block with AF, and this and other drug toxicity should be ruled out before one assumes that structural AV conduction disease is present. In patients with chronic AF, regular R-R intervals may occasionally be caused by “concealed” sinus rhythm (i.e., no evidence of atrial activity because of very-low-amplitude P waves) and not heart block or digitalis intoxication.

The escape rhythm in CHB may be generated by the AV junction, His bundle, bundle branches, or distal conduction system. Rarely, the underlying rhythm arises from the ventricular myocardium or, for all practical purposes, is absent. The site of AV block is important in that it determines to a great extent the rate and reliability of the underlying escape rhythm. The site of origin of the escape rhythm in cases of advanced AV block is more important than the escape rate itself. For example, in heart block associated with inferior AMI or congenital CHB, the escape rhythm is usually generated by the AV junction, and permanent pacing may not be required. Nevertheless, it is worth emphasizing that symptomatic AV block requires pacing regardless of the site, morphology, or rate of the escape rhythm.

Trifascicular block is present when bifascicular block is associated with His-Ventricular interval (HV) prolongation. However, trifascicular block also is often applied loosely to the electrocardiographic patterns of bifascicular block—right bundle branch block (RBBB) plus left anterior hemiblock, RBBB plus left posterior hemiblock, or left bundle branch block (LBBB)—plus first-degree AV block. Using “trifascicular block” to describe these AV conduction disturbances on the ECG is misleading, because the site of block in such cases may be located in the AV node or His-Purkinje system. The P-R interval does not identify patients who have prolonged H-V intervals in such cases. Up to 50% of patients with bifascicular block and prolonged P-R intervals have prolongation of the Atrial-His (A-H) interval (i.e., AV nodal conduction time). Trifascicular block should be used only to refer to alternating RBBB and LBBB, RBBB with a prolonged H-V interval (regardless of the presence or absence of left anterior or posterior fascicular block), and LBBB with a prolonged H-V interval. In addition, the term can be used in a patient with second- or third-degree AV block in the His-Purkinje system with the following: (a) permanent block in all three fascicles, (b) permanent block in two fascicles with intermittent conduction in the third, (c) permanent block in one fascicle with intermittent block in the other two fascicles, or (d) intermittent block in all three fascicles. Thus according to its strict definition, when interpreting an ECG in the absence of a His bundle recording, trifascicular block should be applied only to the patterns of alternating RBBB and LBBB or RBBB with intermittent left anterior and posterior hemiblocks. These situations are class I indications for permanent pacing, even in asymptomatic individuals.

Electrophysiologic Study

Invasive electrophysiologic study (EPS; e.g., His bundle recording) is a useful means of evaluating AV conduction in patients who have symptoms and in whom the need for permanent pacing is not obvious ( Fig. 14-15 ). Electrophysiologic studies (strictly for evaluation of the conduction system and site of block) are not required in patients with symptomatic high-grade or complete AV block recorded on surface ECGs, ambulatory Holter monitoring, or transtelephonic recordings. The need for permanent pacing has already been established in these patients (class I indication). However, EPS may be indicated in patients with high-grade AV block if another arrhythmia is suspected or is a likely cause of symptoms. For example, even if high-grade AV block is documented on spontaneous recordings, ventricular tachycardia may still be the cause of syncope in patients with prior extensive AMI. In patients with alternating BBB, an EPS almost invariably demonstrates a high degree of His-Purkinje system disease. These patients typically have very long H-V intervals and are at very high risk of progression to CHB in a short time. Pacing in these patients is indicated on clinical grounds, and EPS may not be necessary. Electrophysiologic studies are also not indicated in patients whose symptoms are shown not to be associated with a conduction abnormality or block. In addition, patients without symptoms who have intermittent AV block associated with sinus slowing, gradual P-R prolongation before a nonconducted P wave, and a narrow QRS complex should not undergo EPS, given the benign prognosis of these findings.

The incidence of progression of bifascicular block to CHB is variable, ranging from 2% to 6% per year. The method of patient selection affects this incidence, with patients who have asymptomatic bifascicular block progressing to CHB at a rate of 2% per year and patients with symptoms (e.g., syncope or presyncope) progressing at a rate closer to 6% per year.

Many of these studies emphasize the high mortality associated with BBB and bifascicular block. It is worth emphasizing that the mortality associated with the presence of structural heart disease predominantly reflects death resulting from AMI, heart failure, or ventricular tachyarrhythmias rather than bradyarrhythmias.

Three large studies of patients with chronic BBB have been performed to assess the role of His bundle recordings (e.g., H-V interval) to predict progression to CHB. The measurement of the H-V interval represents the conduction time through the His bundle and bundle branches until ventricular activation begins. Because these studies included both asymptomatic and symptomatic patients, care must be taken to ensure that similar patient populations are compared for proper interpretation of these results. Dhingra et al prospectively followed 517 patients with BBB and measured the time required for progression to second- and third-degree block. Only 13% of patients presented with syncope; the others had no symptoms. The cumulative 7-year incidence of progression to AV block was 10% in the group with a normal H-V interval and 20% in the group with H-V interval prolongation. The cumulative mortality rate at 7 years was 48% in patients with a normal H-V interval, and 66% in patients with a prolonged H-V interval. This study emphasized that despite the high mortality associated with the presence of bifascicular block, there is only a low rate of progression to more advanced AV block.

McAnulty et al studied 554 patients with “high-risk” BBB, defined as LBBB, RBBB and left-axis or right-axis deviation, RBBB with alternating left- and right-axis deviation, or alternating RBBB and LBBB. The cumulative incidence of AV block, either type II second-degree or CHB, was 4.9%, or 1% per year, in patients with a prolonged H-V interval and 1.9% in patients with a normal H-V interval (difference not significant). H-V interval prolongation did not predict a higher risk of development of CHB. After entry into the study, 8.5% of patients experienced syncope. The incidence of complete AV block was 17% in patients with syncope versus 2% in patients without a history of syncope.

Scheinman et al studied 401 patients with chronic BBB for about 30 months. This study, in contrast to the Dhingra and McAnulty studies, primarily included patients with symptoms referred for EPS. About 40% of the patients in the Scheinman study had a history of syncope. In patients with an H-V interval of more than 70 msec, the incidence of progression to spontaneous second- or third-degree AV block was 12%. The incidence of complete AV block was 25% for those with an H-V interval of 100 msec or greater. The yearly incidence of spontaneous AV block was 3% in those with a normal H-V interval and 3.5% in those with a prolonged H-V interval.

These findings therefore suggest a relationship between a prolonged H-V interval and development of CHB during the ensuing years in patients with intraventricular conduction disturbances. It also seems that the risk varies directly with the extent of HV prolongation. Symptomatic patients with syncope or presyncope are at much higher risk than asymptomatic patients. The overall risk of CHB in an unselected, symptom-free group of patients with chronic BBB is low (<6%/yr). Current recommendations are not to perform EPS in patients with asymptomatic BBB.

A number of studies evaluated the clinical usefulness of EPS in patients with BBB and syncope. Electrophysiologic studies were performed before the current era of implantable cardioverter-defibrillator (ICD) implantation in patients with syncope and advanced structural heart disease. In one study, 112 patients with chronic BBB and syncope or near-syncope underwent EPS. A normal result predicted a good long-term prognosis. About 25% of patients had a significant conduction system disorder, underwent pacemaker implantation, and experienced recurrence of symptoms at a rate of only 6%. In the study reported by Morady et al, 28% of patients (7 of 32) had sustained, induced monomorphic ventricular tachycardia (VT), whereas about 20% had conduction disturbances at EPS. Six of the seven patients who received pacemakers had no recurrent symptoms.

Thus electrophysiologic studies may be useful in patients with BBB block and syncope for several reasons. First, negative EPS results may identify a group of patients at low risk for cardiac events, especially in the absence of advanced structural heart disease. Induction of sustained VT during EPS identifies patients at risk for life-threatening ventricular arrhythmias who require ICDs. Programmed ventricular stimulation in patients with BBB and syncope may induce bundle branch reentrant VT, which may be readily cured with radiofrequency catheter ablation. Also, EPS identifies patients with advanced conduction system disease (e.g., prolonged H-V interval with BBB) who need pacemakers. In patients with normal ejection fraction and bifasicular block and syncope, electrophysiology studies are no longer recommended. The results of the PRESS study, a multicenter prospective randomized single blinded trial (study registration: NCT01463358) showed that pacemakers reduce symptom recurrences in patients with bivasicular block and syncope when the origin was undetermined after screening. In this trial the annual incidence of rhythm disease development was 7.4%.

The clinical trials that established the role of the ICD for both primary and secondary prevention of sudden death, in addition to cardiac resynchronization therapy, have significantly affected the management of patients with BBB and syncope. Current guidelines recommend ICD implantation in patients with syncope of undetermined etiology in the setting of advanced structural heart disease, because these patients are likely to have an arrhythmic cause of syncope. Thus if LV dysfunction is present ( left ventricular ejection fraction [LVEF] ≤ 35% to 40%) in patients with BBB and syncope, ICD implantation is indicated, and most centers do not perform EPS in these patients. Electrophysiologic studies may still be considered in patients with syncope or near-syncope and BBB with no minimal or mild structural heart disease (LVEF > 40%).

Identifying Patients at Risk for Atrioventricular Block

In patients with symptomatic BBB or bifascicular block, EPS with measurement of H-V intervals have been used for several decades. A “markedly prolonged” H-V interval (≥100 msec) is predictive of development of symptomatic heart block. As noted earlier, Scheinman et al demonstrated that an H-V interval of 100 msec or longer identified a group of patients who had a 25% risk of development of heart block over a mean follow-up of 22 months. According to current guidelines published by the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society Task Force on Practice Guidelines, an H-V interval of 100 msec or longer in an asymptomatic patient documented as an incidental finding on EPS is a class IIa indication for permanent implantation of a pacemaker. Although the finding of a markedly prolonged H-V interval is quite specific, it is very insensitive because H-V intervals of 100 msec or longer are uncommon.

Atrial pacing to stress the His-Purkinje system may provide additional information to identify patients at risk of spontaneous AV block. Healthy subjects do not experience second- or third-degree infra-Hisian block during atrial pacing when the atrial rate is gradually increased, as would occur spontaneously. Certain pacing protocols with abrupt onset of pacing at rapid rates are more likely to induce infra-Hisian block, even in healthy subjects, but even this finding is rare at pacing rates below 150 beats per minute (bpm) in healthy individuals. Because AV nodal dysfunction is frequently seen in patients with significant His-Purkinje system disease, AV nodal block may occur at lower pacing rates than those necessary to demonstrate infra-Hisian block. This “protective” effect of AV nodal dysfunction during resting states may lead to the incorrect conclusion that significant His-Purkinje disease is not present. However, a second trial of atrial pacing after administration of atropine or isoproterenol to facilitate AV nodal conduction may demonstrate infra-Hisian block. Dhingra et al reported a 50% rate of progression to type II or complete AV block in patients in whom block develops distal to the His bundle at paced rates of less than 150 bpm. In a later study, Petrac et al evaluated 192 patients with chronic BBB and syncope, of whom 18 (9%) had incremental atrial pacing–induced infra-Hisian second-degree AV block at a paced rate of 150 bpm or less (mean pacing rate, 112 ± 10 bpm). During a mean follow-up of 68 ± 35 months, 14 of the 18 patients (78%) demonstrated spontaneous second- or third-degree AV block, confirming that this abnormal finding identifies a subgroup at a high risk for development of heart block. As with an H-V interval of 100 msec or less, however, His-Purkinje block during incremental atrial pacing at physiologic rates is uncommon in patients with BBB and syncope. According to current guidelines, if atrial pacing–induced infra-Hisian block that is “not physiologic” is demonstrated as an incidental finding on EPS, permanent pacing is recommended (class IIa indication).

Provocative drug tests have been suggested as another means of evaluating the distal conduction system ( Fig. 14-16 ). Pharmacologic stress testing may be considered in patients with BBB and syncope who have a baseline H-V interval of 70 msec or higher (but <100 msec) and no infra-Hisian block demonstrated. Data describing the experience with intravenous type Ia (procainamide, ajmaline, disopyramide) or type Ic (flecainide) antiarrhythmic drugs are limited. Only intravenous procainamide is available in the United States. Administration of these agents may result in a marked increase in the H-V interval (>15 to 20 msec), an H-V interval greater than 100 msec, or precipitation of spontaneous type II second- or third-degree AV block, all of which may indicate a higher risk for development of CHB. Tonkin et al administered procainamide at a dose of up to 10 mg/kg to 42 patients with BBB and syncope, and produced intermittent second- or third-degree His-Purkinje block or H-V prolongation to more than 15 msec during sinus rhythm in 11 patients (26%). However, only 2 of the 11 patients (18%) with a positive result had documented high-grade AV block during 38 months of follow-up, and 3 of 5 asymptomatic control patients with BBB (60%) had a positive procainamide challenge test result. Other studies of class I antiarrhythmic drug testing to stress the His-Purkinje system likewise have limited patient numbers, lack adequate control groups or follow-up, and seem to indicate that pharmacologic testing has low predictive value. Current permanent pacing guidelines do not include a recommendation regarding the need for permanent pacing on the basis of results of pharmacologic stress testing of the His-Purkinje system.

Electrophysiologic testing has recognized limitations for identifying patients with significant AV nodal or His-Purkinje dysfunction. Although finding an abnormality on EPS may be helpful, its sensitivity is low and cannot be used alone to exclude a significant AV conduction disturbance. In a small study by Fujimura et al, 13 patients with documented symptomatic transient second- or third-degree AV block referred for implantation of a permanent pacemaker underwent AV conduction testing at pacemaker insertion. These tests included facilitation of AV nodal conduction with atropine and pharmacologic stress of His-Purkinje conduction with low doses of procainamide. Surprisingly, only 2 of the 13 patients showed significant abnormalities in the AV conduction system (inducible infra-Hisian block in both cases) during EPS yielding a sensitivity of 15.4%. Two other patients had moderately prolonged H-V intervals, although much shorter than 100 msec. If these two patients are included in the diagnostic data, the sensitivity of EPS is increased to 46%, raising important questions about EPS sensitivity for identifying patients at risk for symptomatic AV block.

First-Degree Atrioventricular Block

The prognosis and natural history in patients with primary first-degree AV block and moderate PR prolongation traditionally have been thought of as being benign. Progression to CHB over time occurred in about 4% of patients in the study by Mymin et al, which involved only young, male U.S. Air Force pilots. Most of the patients (66%) had only mild to moderate PR prolongation, to about 0.22 to 0.23 second. In the great majority of subjects, the P-R interval remained within a narrow range, changing by less than 0.04 second. More recently, a Framingham Heart Study report challenged the long-held belief that first-degree AV block has a benign prognosis. In this large, community-based sample with long-term follow-up, patients with first-degree AV block (PR > 200 msec) at baseline were at substantially increased risk of future AF (about twofold) and pacemaker implantation (about threefold), and a moderately increased risk of all-cause mortality, compared with individuals without first-degree AV block.

Patients with a “markedly prolonged” P-R interval may or may not be symptomatic at rest but may demonstrate a pseudo-pacemaker syndrome caused by AV dyssynchrony, particularly during exertion. These events are more likely to become symptomatic during exercise, because the P-R interval may not shorten appropriately as the R-R interval decreases. Zornosa et al described PR prolongation after radiofrequency ablation resulting from injury of the fast-AV nodal pathway in patients with AV nodal reentry. Symptoms caused by long P-R intervals resolved after DDD pacing was performed.

Implantation of permanent pacemakers is reasonable in patients with first-degree AV block with symptoms similar to those of pacemaker syndrome or hemodynamic compromise (class IIa indication). Previous versions of the ACC/AHA/HRS guidelines required documentation of alleviation of symptoms with temporary AV pacing before permanent pacing. However, this requirement was removed in the subsequent revisions of the guidelines, in part because a temporary AV pacing study may not demonstrate symptomatic improvement at rest, and is often impractical to perform during exercise. Thus it is reasonable to institute permanent pacing in symptomatic patients with extremely long P-R intervals (≥0.30 sec) that do not shorten during exercise. Permanent pacemaker implantation may also benefit patients with left ventricular (LV) systolic dysfunction, congestive heart failure, and marked first-degree AV block (>0.30 sec) in whom a shorter A-V interval results in hemodynamic improvement. An acute study in patients with first-degree AV block suggested that systolic performance measured using a Doppler echocardiography–derived aortic flow time-velocity integral, improved after institution of DDD pacing at a rate of 70 bpm if the intrinsic AV conduction time (A-R interval) was longer than 0.27 second. The optimal AV delay in this study was 159 ± 22 msec, which is consistent with most other studies, in that the optimal AV delay is about 150 msec at rest. However, given the need for frequent ventricular pacing support to optimize the A-V interval in these patients, atrio-biventricular pacing is likely to be the optimal long-term pacing mode in these patients with LV systolic dysfunction and heart failure. In a trial comparing atrial pacing versus ventricular backup only pacing in 1030 patients with indications for ICDs, Sweeney et al reported an increased incidence of heart failure hospitalizations or death in patients with prolonged PR interval >0.23 second, in patients randomized to atrial pacing compared with ventricular pacing. This difference was attributed to increase in left-sided AV desynchronization. In patients undergoing transcatheter aortic valve replacement (TAVR), first-degree AV block at baseline was a predictor for permanent pacemaker implantation especially in patients undergoing Medtronic CoreValve Revalving system compared with Edwards SAPIEN valve (RR 1.52; P < 0.01).

Second-Degree Atrioventricular Block

Controversy surrounds the prognosis and need for permanent pacing in patients with chronic type I second-degree AV block in the presence of a narrow QRS complex. Some consider this condition benign only in young people or athletes without organic heart disease. The natural history of 56 patients with chronic type I second-degree AV block, some of whom were younger than 35, or were well-trained athletes, was described in 1981 by Strasberg et al. They concluded that progression to CHB is relatively uncommon in this patient population, and this finding carries a benign prognosis in the absence of structural heart disease. In 1985, however, Shaw et al suggested that patients with type I second-degree AV block have a worse prognosis than age- and gender-matched individuals, unless the patients already had permanently implanted pacemakers. The 214 patients with chronic second-degree AV block (mean age, 72) were divided into three groups—type I block (77), type II block (86), and 2 : 1 or 3 : 1 block (51)—and monitored over a 14-year period. The 3- and 5-year survival rates were similarly poor, regardless of the type of AV block. Patients with type I block without BBB fared no better than those with type II block. Patients with type I second-degree AV block, who received permanent pacemakers, had survival similar to that of an age- and gender-matched control population.

In 1991 the British Pacing and Electrophysiology Group (BPEG) suggested that pacing should be considered in adults in whom type I second-degree AV block occurs during much of the day or night, regardless of the presence or absence of symptoms. In 2004, Shaw et al reported again on the prognosis of patients with type I second-degree AV block and once again concluded that type I second-degree AV block is not a benign condition in patients 45 years or older. The majority of their patients with type I second-degree AV block who were 45 years or older progressed to higher-degree AV block, experienced symptomatic bradycardia, or died prematurely if they did not receive pacemakers. These investigators recommended pacemaker implantation in patients with type I second-degree AV block even in the absence of symptoms or structural heart disease, except in those younger than 45. According to current ACC/AHA/HRS guidelines, however, permanent pacemaker implantation in asymptomatic type I second-degree AV block that is at the supra-His (AV node) level or is not known to be intra-Hisian or infra-Hisian is considered insupportable by current evidence (class III indication). It seems prudent, on the basis of available data, at least to monitor closely any elderly patient with asymptomatic type I AV block or 2 : 1 AV block with narrow QRS complexes, because these electrocardiographic abnormalities may be markers for progressive conduction system disease.

The natural history of asymptomatic type II second-degree AV block initially was addressed in a University of Illinois study reported in 1974 that found most patients experienced symptoms within a relatively short period. In 1985 Shaw et al reported that 86 patients (mean age, 74) monitored between 1968 and 1982 with chronic Mobitz type II second-degree heart block had a 5-year survival rate of 61%. The 5-year survival of those who underwent permanent pacemaker implantation was significantly better than those who did not. These observations form the basis for recommendations to institute permanent pacing in all patients with type II second-degree AV block, regardless of symptoms (class IIa indication with a narrow QRS; class I recommendation with a wide QRS).

Complete Heart Block

The natural history of spontaneously developing asymptomatic CHB in adult life predates pacemaker therapy. Currently, almost all adult patients with CHB eventually have symptoms and undergo pacemaker placement. Several studies in the 1960s emphasized the poor prognosis of patients with CHB. The 1-year survival rate of patients who experienced Stokes-Adams attacks caused by CHB and who did not receive pacing was only 50% to 75%, significantly less than that of a gender- and age-matched control population. The “best” prognosis was in patients with an idiopathic or unknown cause of CHB. At least 33% of deaths were related to CHB and Stokes-Adams attacks. These differences in survival persisted even after 15 years of follow-up and appear to be related to the considerably higher incidence of sudden death. Some debate whether the presence of syncope is associated with a worse prognosis in patients with documented CHB. The prognosis for transient CHB was poor as well, with 36% 1-year mortality reported in at least one 1970s study. Whether this poor prognosis applies now to patients with transient CHB who have not received pacing is unknown.

Edhag and Swahn reported in the 1960s and 1970s on the long-term prognosis of 248 patients with high-grade AV block, most of whom had CHB, with a mean 6.5 years of follow-up. The mean age at pacemaker implantation was 66, and the 1-year survival of patients who received pacemakers was 86%, versus 95% for an age- and gender-matched group of Swedish patients. After the first year, survival in the patients with pacemakers was similar to that in the general population. Edhag compared survival in different age groups, found no difference in survival between elderly patients with heart block who underwent permanent pacing, and the age- and gender-matched general population. In contrast, younger patients with heart block had a higher mortality than did the controls, even after pacing. This higher mortality likely is a reflection of the underlying structural heart disease responsible for high-grade AV block.

Complete heart block can be described as acute or chronic depending on its onset. Acute AV block associated with myocardial ischemia is rare, but may occur and result in transient AV block. High-grade AV block is strictly defined as 3 : 1, 4 : 1, or higher AV ratios in which AV synchrony is intermittently present. As in complete AV block, high-grade AV block may be localized anywhere in the conduction system ( Fig. 14-17 ). In some patients, high-grade AV block may be present at multiple levels in the conduction system. Generically “high-grade AV block” has been used to describe any form of AV block that suggests an increased risk for CHB or symptomatic bradycardia. This typically includes type II second-degree block, 2 : 1 AV block, strictly defined high-grade AV block, and CHB. The generic use of high-grade AV block is best avoided, because the multiple forms of AV block included have variable pathogeneses and prognoses that blur the clinical usefulness of the term.

Complete AV block can be classified as congenital or acquired. In patients with acquired complete AV block, the site of block is localized distal to the His bundle in about 70% to 90% of patients, to the His bundle in 15% to 20%, and within the AV node in 16% to 25%. In patients with congenital complete AV block, the escape rhythm is more often found in the proximal His bundle or AV node.

Paroxysmal Atrioventricular Block

Paroxysmal AV block is defined as the sudden occurrence, during a period of 1 : 1 AV conduction, of a block of sequential atrial impulses resulting in a transient total interruption of AV conduction. Thus it is the onset of a paroxysm of high-grade AV block associated with a period of ventricular asystole before conduction returns or a subsidiary pacemaker escapes. Paroxysmal AV block may occur in a variety of clinical conditions but has been described most often in association with vagal reactions, such as during vomiting, coughing, or swallowing, after urination, or with abdominal pain, carotid sinus massage, coronary angiography, or head-up tilt-table testing. Patients with neurally mediated syncopal syndromes may have transient heart block, typically with associated sinus slowing. On the other hand, paroxysmal AV block also may occur in patients with severe, distal conduction disease. This may manifest as tachycardia-dependent AV block in the His-Purkinje system (also called phase 3 or voltage-dependent block) during or after exertion; manifested as the abrupt onset of bradycardia or AV block after a pause (phase 4 block); and as type II second-degree AV block. Paroxysmal AV block in these patients (not related to vagal AV block) is a marker for His-Purkinje disease with an unpredictable escape mechanism. Permanent pacemaker implantation in these patients (with the possible exception of block mediated by acute myocardial ischemia) is almost always indicated.

One report described the clinical experience in 20 patients (mean age, 63 ± 14 years) with paroxysmal AV block seen at a single institution over a 12-year period. Paroxysmal AV block in these patients was related to a vagal reaction, AV-blocking drugs, or distal conduction disease. The AV block in these patients lasted from 2.2 to 36 seconds. Fifteen patients experienced syncope, and one patient had bradycardia-induced polymorphic VT that required electrical cardioversion. About one half of the patients had structural heart disease and a wide QRS duration.

Idiopathic Paroxysmal Atrioventricular Block

The common clinical and electrophysiologic features define a distinct form of syncope characterized by a long history of recurrent syncope as a result of idiopathic paroxysmal AV block with long pauses, absence of cardiac and ECG abnormalities, absence of progression to persistent forms of AV block, and efficacy of cardiac pacing therapy. These patients show an increased susceptibility to exogenous adenosine. In these patients the AV block was never initiated by atrial, His, or ventricular premature extrasystole, increased heart rate (tachy-dependent AV block), or decreased heart rate (brady-dependent AV block); all features that support a diagnosis of intrinsic AV block. In addition, there is no gradual slowing of the sinus rate (P-P interval) or AV conduction (prolonging PR) suggestive of vagal effect in these patients. Permanent pacemakers are effective in preventing syncope in these patients.

Bundle Branch Block

Most patients with chronic BBB or bifascicular block have underlying structural heart disease (prevalence, 50% to 80%). Historically, it was believed that progression from chronic bifascicular block to trifascicular block was common. Retrospective studies in patients with chronic bifascicular block suggested that the risk of progression to complete AV block was 5% to 10% per year. In the early 1980s, the results of several large prospective studies questioned assumptions about the incidence and clinical implications of the progression of conduction system disease in this patient population. Prospective studies of groups of symptom-free patients with bifascicular block who were found to have prolonged H-V intervals on EPS showed that such patients are at increased risk for CHB, but that the absolute risk remains very low, about 1% to 2% per year. McAnulty et al found that the risk for development of CHB was 5% in 5 years. A prolonged H-V interval was associated with higher values for both total cardiovascular mortality and sudden death. Prolonged H-V interval is likely associated with more extensive structural heart disease. Furthermore, these studies demonstrated that in the absence of symptoms, routine His bundle recordings are of limited usefulness in patients with bifascicular block. Asymptomatic individuals with chronic BBB need no further evaluation than an ECG.

On the other hand, patients with syncope and bifascicular block represent a different clinical problem. If a thorough clinical evaluation, including a history, physical examination, and ECG, does not uncover a cause of syncope, pacing is indicated based on the PRESS study. Linzer et al found that the presence of first-degree AV block or BBB increased the odds ratio of finding abnormalities suggesting risk of bradyarrhythmia (predominantly heart block) by threefold to eightfold during EPS in patients with unexplained syncope ( Table 14-1 ). Electrophysiologic studies may uncover other causes of syncope, such as sinus node dysfunction, rapid supraventricular tachycardias, and inducible monomorphic VT. In some studies, monomorphic VT was inducible in at least 30% of patients with BBB and syncope. A minority of patients are found to have a markedly prolonged H-V interval, abnormal or fragmented His bundle electrogram, or block distal to the His bundle with atrial pacing, suggesting the need for implantation of a permanent pacemaker.

Congenital Atrioventricular Block

Congenital CHB traditionally was diagnosed in the first month after birth in a child in whom a slow heart rate was detected, and certain infectious etiologies rarely seen today, such as diphtheria, rheumatic fever, and congenital syphilis, were excluded. Currently with fetal echocardiography many cases are diagnosed in utero and, if associated with structural heart disease, are related to a high rate of fetal death. The incidence of congenital CHB is estimated to be 1 in 15,000 to 22,000 live births. More than one half of fetuses found to have congenital CHB have structural heart disease, including congenitally corrected transposition of the great arteries, and often have a poor prognosis in infancy. When congenital CHB is detected in utero in a child with a structurally normal heart, the condition is frequently associated with intrauterine exposure to maternal autoantibodies Ro and La (i.e., neonatal lupus); this situation has a better prognosis than the presence of congenital heart disease. The development of AV block in a child with a structurally normal heart is uncommon, but should not be confused with congenital CHB. Childhood-onset heart block often is presumed to be caused by viral myocarditis. In patients with congenital CHB, the mean resting heart rate is between 40 and 60 bpm, but decreases with age.

Although controversial in the past, the indications for permanent pacemaker implantation in young patients with congenital CHB have evolved on the basis of improved understanding of the natural history of the disease. Current guidelines indicate that permanent pacemaker implantation should be performed for congenital CHB patients with a wide QRS escape, complex ventricular ectopy, ventricular dysfunction, a ventricular rate less than 55 bpm, or congenital heart disease and a ventricular rate less than 70 bpm (class I indications). Permanent pacemaker implantation may also be considered for patients after the first year of life with an average heart rate less than 50 bpm, abrupt pauses in heartbeat that are two or three times the basic cycle length, or associated with exercise intolerance caused by chronotropic incompetence (class IIa indications).

In asymptomatic children or adolescents with an acceptable rate, a narrow QRS complex, and normal ventricular function, a permanent pacemaker also may be considered (class IIb). Pacemaker implantation in asymptomatic patients with congenital CHB is associated with improved long-term survival and prevention of syncope. However, it must be recognized that ventricular dysfunction caused by RV pacing–associated dyssynchrony may occur years or decades after pacemaker implantation. A 2004 study demonstrated that long-term transvenous RV apical pacing was associated with deleterious LV remodeling and reduced exercise capacity after 10 ± 3 years of follow-up in patients with congenital CHB. Therefore these patients require periodic evaluation of ventricular function after pacemaker implantation. In addition, alternative ventricular pacing sites, including RV septum and left ventricle, have been proposed in patients with congenital CHB, who may require many decades of ventricular pacing but have not been definitively defined. Ventricular dysfunction in this setting may result from myocardial autoimmune disease in association with RV pacing–induced ventricular dyssynchrony. Interestingly, a recent study suggests that the natural history of patients with isolated congenital CHB who require pacing depends on their antibody status. Antinuclear antibody (ANA) status was a predictor for the development of heart failure and death. Long-term RV pacing was not associated with development of congestive heart failure, deterioration in ventricular function, or reduced survival in congenital AV block patients without ANAs.

Inherited Conduction System Diseases

Inherited causes of AV conduction disturbances have been increasingly recognized and better understood over the last several decades. The genetics of conduction disease represents an exciting new development in our understanding of the AV conduction system. Familial clustering in cases of “idiopathic” conduction system degeneration is consistent with a hereditary basis. Some cases with familiar clustering have an autosomal dominant pattern of inheritance and associated congenital heart malformations and cardiomyopathy. Inherited conduction system disease may be isolated or associated with congenital heart diseases, neuromuscular disorders, and cardiomyopathies. Inherited conduction diseases include developmental transcription factor mutations, cardiac ion channelopathies, and mutations in genes regulating energy metabolism, gap junctions, and structural proteins.

Mutations in genes encoding cytoskeletal and nuclear membrane proteins are involved in the muscular dystrophies, including myotonic dystrophy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy type 1B. All these neuromuscular disorders may be associated with cardiac conduction defects. Myotonic dystrophy is the most common form of muscular dystrophy. This autosomal dominant inherited disorder is caused by an expansion of cytosine-thymine-guanine repeat on chromosome 19. High-degree AV block and BBB are the most common conduction system defects. A mouse knockout model of the myotonic dystrophy protein kinase displays first-, second-, and third-degree AV block. The mechanism of AV nodal pathology is thought to be caused by alterations in the activation kinetics or amplitude of the L-type calcium current (I _Ca,L ).

Mutations in the gene encoding for the inner nuclear membrane protein lamin A/C (LMNA) cause Emery-Dreifuss muscular dystrophy with conduction system defects. Progressive conduction disease is present in virtually all cases and leads to the need for permanent pacing. LMNA also is implicated in a variety of other diseases including Hutchinson-Gilford syndrome, mandibuloacral dysplasia, Charcot-Marie-Tooth disease–type atypical Werner's syndrome, and the Dunnigan type familial partial lipodystrophy, most of which also are associated with cardiac conduction system defects. Lamin A/C is necessary for the structural integrity of the nucleus; in the presence of LMNA mutation, myocardial cells exposed to mechanical stress undergo cell damage. LMNA mutations also are associated with dilated cardiomyopathy, with AV conduction defects referred to as “laminopathy.” Otomo et al described a large Japanese family with 21 of 224 members affected by this genetic defect, which manifests clinically as progressive AV block, dilated cardiomyopathy, heart failure, and sudden death. EPS in affected individuals demonstrated AV nodal dysfunction (marked prolongation of A-H interval) and normal HV and QRS durations. Histologic evaluation of postmortem heart specimens from affected members showed preferential degeneration, with replacement by fibrofatty tissue of the AV nodal region. Patients may die suddenly at a young age. Of note, there may be a gender difference in the severity of the cardiac phenotypes seen in lamin A/C disease. Males often have significant cardiac disease, with moderate or severe LV dysfunction developing in the first two to three decades of life, whereas females with the same mutations are more likely to have progressive conduction disease with less severe LV dysfunction.

Cardiac Sodium Channel and Conduction Disorders

The α-subunit of the sodium channel is known as Nav1.5 and is coded by the SCN5A gene in the short arm of the chromosome 3 (3p21). It consists of four homologous domains known as DI to DIV joined by so-called linkers ( Fig. 14-18 ). Nav1.5 is primarily responsible for phase 0 of the action potential, causing rapid depolarization as the channel opens and sodium ions enter the myocyte. Disruptions in Nav1.5 function result in impaired channel reactivation or expression that may affect the ability to conduct action potentials along and between myocytes. The channel then becomes inactivated by slow- and fast-inactivation conformational changes. Mutations in the cardiac-specific sodium channel gene (SCN5A) have been associated with progressive cardiac conduction system disease (PCCD) also referred to as Lev or Lenègre disease. It is a relatively common cardiac conduction disorder characterized by age-dependent progressive delay in the propagation of the cardiac impulse through the His-Purkinje system with RBBB or LBBB, eventually resulting in complete AV block. Patients with classic Lev disease demonstrate fibrosis within the proximal His bundle, whereas those diagnosed with Lenègre disease often demonstrate fibrosis within the more distal bundle branches and Purkinje fibers. SCN5A is the first gene associated with PCCD described in 1999 by Schott and colleagues. Interestingly SCN5A mutations can produce a variety of other phenotypes, including Brugada syndrome, congenital type 3 long QT syndrome (LQTS), idiopathic ventricular fibrillation, congenital sick sinus syndrome, AF, and dilated cardiomyopathy. An overlap syndrome involving a mutation in the cardiac sodium channel is associated with conduction system disease along with LQTS and Brugada syndrome. Homozygous mutations in the SCN5A gene can cause a highly lethal combination of LQTS and 2 : 1 AV block in infants. SCN5A mutations reduce cardiac sodium current, resulting in decreased action potential upstroke velocity and slowed impulse propagation mainly in fast-conducting sodium channel–dependent conduction tissue. SCN5A mutation carriers often have long P waves and prolonged P-R and QRS intervals with normal A-H and prolonged H-V intervals, indicative of infra-Hisian delays. At present several SCN5A mutations seem to be causally related to inherited cardiac conduction system disease. These mutations have a wide variety of effects on gene expression or channel function ( Table 14-2 ). A novel SCN5A mutation involving a heterozygous single-nucleotide mutation resulted in an amino acid substitution (A1180V) in a three-generation Chinese family. The mutation causes a negative shift of voltage-dependent inactivation of the cardiac sodium channels with slower recovery leading to a rate-dependent sodium current reduction, and a moderate increase in late sodium current. The A1180V mutation was associated with familial, progressive, adult-onset AV block in the third decade of life that preceded the subsequent development of dilated cardiomyopathy. Interestingly early signs of the sodium channel defect in unaffected carriers of the pedigree were detected in the ECG manifested by QRS widening at high heart rates and QTc prolongation at rest. This suggests a possible opportunity for early diagnosis of the mutation before development of a clinically significant conduction system defect or cardiomyopathy, even in the absence of a genetic test. Mutations in β-subunit–encoding genes are found in individuals with various arrhythmic phenotypes. Different mutations in the cardiac sodium channel β1-subunits (W179X, E87Q) have also been associated with cardiac conduction disease.

The nonselective transient receptor potential melastatin 4 (TRPM4) cation channel is abundantly expressed in cardiac cells, being involved in several aspects of cardiac rhythmicity, including cardiac conduction, pacemaking and action-potential repolarization. The TRPM4 channel mediates a Ca ²⁺ -activated nonselective cationic current (I _NSCca ). Dominantly inherited mutations in the TRPM4 gene are associated with the cardiac bundle-branch disorder progressive familial heart block type I (PFHBI) and isolated cardiac conduction disease (ICCD), giving rise to atrioventricular conduction block (AVB), RBBB, bradycardia, and the Brugada syndrome. The mutant phenotypes closely resemble those associated with mutations in the SCN5A gene, encoding the voltage-gated Na ⁺ channel NaV1.5. These observations and the unexpected partnership with sulfonylurea receptors (SURs) make the TRPM4 channel a promising novel target for treatment of cardiac disorders.

Defects in potassium channel genes may be a molecular basis for some inherited AV conduction disturbances in humans. The LQT7 syndrome, or Andersen-Tawil syndrome, is caused by mutations in the KCNJ2 encoding an inward rectifier potassium channel Kir2.1 and is another cardiac ion channelopathy associated with conduction system disorders. Andersen-Tawil patients may present with conduction abnormalities, such as AV block, BBB, or intraventricular conduction delay. This syndrome is characterized by potassium-sensitive periodic paralysis, ventricular arrhythmias, and dysmorphic features. A molecular defect in KCNQ1, the pore-forming α-subunit of the I _KS potassium channel, also may be a causative mutation responsible for AV conduction disease. An S140G mutation in KCNQ1 has been genetically linked in a Chinese family to AF and to a slow ventricular response in AF as a manifestation of AV conduction disease. Thirteen of 16 AF patients in the family with the KCNQ1 S140G mutation had a slow ventricular response in AF, with a mean heart rate less than 60 bpm in the absence of AV nodal–blocking medications. In addition, a transgenic mouse model with myocardium-specific expression of the human KCNQ1 S140G mutation manifested frequent episodes of first-, second-, advanced-, or third-degree AV block. Timothy syndrome is a rare variant of long QT syndrome (LQTS8) caused by CACNA1 _C mutation and is associated with dysmorphic features, congenital heart malformations, 2 : 1 AV block, and high risk for sudden death.

Several mutations in genes encoding proteins that regulate septation of the heart have been associated with conduction system disease. In addition to conduction disease, this phenotype includes atrial or ventricular septal defects. The Nkx2.5 homeobox gene is critically involved in development of the cardiac conduction system. Loss-of-function mutations in the homeobox transcription factor Nkx2.5 cause a loss of DNA-binding activity of this gene. These mutations are associated with progressive AV node dysfunction and other diffuse conduction system abnormalities. Studies in Nkx2.5 -deficient mice have shown that Nkx2.5 insufficiency perturbs the conduction system during development, resulting in hypoplasia of the AV node, His bundle, and Purkinje system. Mutations in the T-box transcription factor Tbx5, which similarly is an important early regulator of cardiac development, cause Holt-Oram syndrome. This syndrome is manifested by congenital heart disease (usually secundum-type atrial septal defects) associated with progressive AV block and upper limb deformities. Less often patients with Holt-Oram syndrome have structurally normal hearts, and clinically manifest with only AV block and subtle hand malformations. Another transcription factor associated with conduction system defects is HF-1b, an Sp1-related transcription factor preferentially expressed in the cardiac conduction system and ventricular myocytes. Mice deficient for HF-1b are prone to sudden death and have AV block. Downregulation of the gap-junction protein connexin 40 (Cx40) has been hypothesized as a unifying genetic mechanism responsible for the AV conduction defects in Nkx2.5, Tbx5, and HF-1b transcription factor mutations.

Mutations in the PRKAG2 gene, which encodes for a regulatory subunit of adenosine monophosphate (AMP)-activated protein kinase involved in intracellular energy metabolism, are found in association with a familial form of the Wolff-Parkinson-White (WPW) syndrome. However, high-grade AV block is the dominant clinical rhythm disturbance associated with this genetic defect. PRKAG2 gene mutations are characterized by pseudohypertrophy of the left and right ventricles caused by glycogen deposition in cardiac muscle. Ventricular preexcitation is thought to be caused by anulus fibrosis disruption and glycogen deposition, distinct from the muscular-appearing bypass tracts observed in typical WPW syndrome. The index of suspicion for PRKAG2 disease should be raised when massive LV wall thickening (>30 mm) is present in association with high-grade AV block. A mouse model carrying a mutation responsible for the human disease has been generated.

Many of the metabolic storage disorders that have a genetic basis, including Pompe disease, Anderson-Fabry disease, and Danon disease, are associated with cardiac involvement that includes prominent AV conduction disturbances. These diseases may also display abnormal electrical AV connections similar to the ventricular preexcitation seen in PRKAG2 disease.

Mitochondrial disorders comprise a group of diverse genetic diseases, with cardiac conduction defects reported in 10% to 40% of the patients with these disorders. Kearns-Sayre syndrome (ophthalmoplegia plus), which involves large mitochondrial DNA deletions, consists of the triad of complete AV block, chronic progressive external ophthalmoplegia, and pigmentary degeneration of the retina. It can present with AV block and dilated cardiomyopathy, along with muscle weakness, central nervous system dysfunction, and endocrinopathies. The conduction defects typically involve the distal His bundle, bundle branches, and infranodal conduction. The accelerated and unpredictable rate of progression to complete AV block, together with an associated mortality of up to 20%, should lead to routine evaluation of patients with Kearns-Sayre syndrome for AV conduction disturbances, and electrocardiographic screening of family members. Current guidelines advocate pacemaker implantation in patients with Kearns-Sayre syndrome with ECG changes indicative of conduction defects, with or without symptoms, because of the unpredictable progression of AV conduction disease in this syndrome ( Tables 14-3 and 14-4 ).

Acquired Causes of Atrioventricular Block

Acquired AV block may be secondary to a number of causes of generalized myocardial scarring (see Table 14-3 ). These causes include atherosclerosis, dilated cardiomyopathy, hypertension, infiltrative cardiomyopathies, inflammatory disorders, and infectious diseases. In most cases the specific etiology is clinically unknown, and with few exceptions (e.g., Lyme disease, endocarditis, and sarcoidosis) is relatively unimportant from a therapeutic point of view. The most common cause of chronic acquired AV block is related to aging of the cardiac cytoskeleton. An entity known as idiopathic bilateral bundle branch fibrosis, or Lev disease, is characterized by slowly progressive replacement of specialized conduction tissue by fibrosis, resulting in progressive fascicular block and BBB. Lev proposed that damage to the proximal LBB and adjacent main bundle or main bundle alone is the result of an aging process exaggerated by hypertension and arteriosclerosis of the blood vessels supplying the conduction system. Another variant of idiopathic conduction system disorder is Lenègre disease, which occurs in younger patients and is characterized by loss of conduction tissue, predominantly in the peripheral parts of the bundle branch. As noted, some cases previously classified as “idiopathic” conduction disease, especially when there is familial clustering, may have a genetic cause for the conduction disease.

Patients with sick sinus syndrome are known to be at risk for concomitant symptomatic heart block. The block may be caused by progressive fibrodegenerative disease extending from the sinus node region to the AV conduction system. The relative frequency of this association varies between studies. Rosenqvist and Obel pooled the data from 28 published studies and reported a mean incidence for development of second- or third-degree AV block of 0.6% per year (range, 0 to 4.5%/yr) in patients in whom permanent atrial pacemakers have been implanted for symptomatic sinus node dysfunction. The total prevalence of second- or third-degree AV block was 2.1% (range, 0 to 11%). In a retrospective review of 1395 patients with sick sinus syndrome monitored for a mean of 34 months, Sutton and Kenny estimated that the annual incidence for development of conduction system diseases was 3%; such conduction diseases included significant first-degree AV block, BBB, HV prolongation, and a low Wenckebach heart rate. Thus AV conduction system disease occurs relatively frequently in patients with sinus node dysfunction. Similarly, sinus node dysfunction, particularly chronotropic incompetence, may occur frequently in patients with acquired CHB.

Complete AV block may occur after cardiac surgical or interventional catheter-based procedures. CHB occurs more often (3% to 6% incidence) after replacement of aortic, mitral, or tricuspid valves, given the proximity of their anuli to the AV junction, than after isolated coronary artery bypass graft (CABG) surgery, in which the incidence is less than 1% to 2%. CHB is often seen after surgical procedures to repair ventricular septal defects, tetralogy of Fallot, AV canal defects, or subvalvular aortic stenosis. Heart block is also a potential complication of septal myomectomy and catheter-based septal ablation to relieve LV outflow tract obstruction in hypertrophic cardiomyopathy. The incidence of heart block requiring permanent pacing after alcohol septal ablation varies from 10% to 33%.

Baerman et al investigated the time course of conduction defects after bypass surgery. Surgical technique consisted of cold, hyperkalemic cardioplegia, and conduction defects resolved partially or completely in 50% of patients. Patients with conduction defects generally had longer cardiopulmonary bypass times, longer aortic cross-clamp times, and more vessels requiring bypass. In three of the four patients with CHB, the heart block eventually resolved after discharge and implantation of a permanent pacemaker. Reasons for conduction abnormalities after cardiac surgery include ischemic injury to the conduction system, direct surgical manipulation or trauma to conduction tissue, traumatic disruption of the distal conduction system, edema, dissecting hematomas, and alterations in conduction caused by cardioplegia.

Surgery for correction of valvular heart disease often leads to conduction defects. After discontinuation of cardiopulmonary bypass, a variety of cardiac rhythm disturbances may be seen, including sinus arrest, junctional rhythm, BBB, AV block, and sinus bradycardia. Many of these rhythm disturbances are transient, resolving within 5 to 7 days. Transient BBB is quite common, occurring in 4% to 35% of patients and generally resolving within 12 to 24 hours. In one study, newly acquired, persistent BBB developed in 15.6% of patients after aortic valve replacement and was associated with a higher adverse event rate. The investigators recommended that prophylactic implantation of a pacemaker be considered soon after surgery in patients who demonstrate persistent BBB. Conduction disturbances are particularly common both in patients with aortic valve disease and after aortic valve replacement, with 5% to 30% of patients experiencing some conduction abnormality after valve replacement. Most of these abnormalities are transient; however, chronic CHB may occur. Postoperative AV block that is not expected to resolve after cardiac surgery is a class I indication for permanent pacing. The incidence of conduction disorders requiring permanent pacing in patients after aortic valve replacement is 3% to 6%.

Intraoperative heart block does not predict the need for permanent pacing. One study found that risk factors for irreversible AV block requiring permanent pacemaker implantation after aortic valve replacement were previous aortic regurgitation, myocardial infarction, pulmonary hypertension, and postoperative electrolyte imbalance. In another study, Koplan et al developed and validated a preoperative risk score to predict the need for permanent pacing after cardiac valve surgery, using a large database of surgical patients at a single institution (1992-2002). Preoperative predictors of the need for permanent pacing after cardiac valve surgery were age over 70, previous valve surgery, multivalve surgery (especially tricuspid), preoperative BBB (especially RBBB), and first-degree AV block. The incidence of permanent pacemaker implantation ranged from 25% in high-risk patients to 3.6% in low-risk patients, with risk based on preoperative variables. Glikson et al showed that postoperative complete AV block was the most important predictor of subsequent pacemaker dependency. They recommended earlier decisions on the timing of permanent pacemaker implantation, by the sixth postoperative day in patients with a wide QRS escape rhythm, and by the ninth day in patients with a narrow QRS rhythm. In most institutions, permanent pacing would be instituted earlier, probably by the fourth to sixth postoperative day.

Transcatheter aortic valve replacement (TAVR) is a rapidly evolving technology for severe, calcific aortic stenosis. The incidence of CHB requiring permanent pacemaker following TAVR is significantly higher than the approximate 5% following surgical aortic valve replacement. Two TAVR devices are most currently in clinical use in North America: the Edwards SAPIEN valve (ESV, Edwards Lifesciences Corp, Irvine, CA), and the CoreValve Revalving system (CV, Medtronics, Minneapolis, MN). A recent meta-analysis of 41 studies, including 11,210 patients undergoing TAVR, showed that 17% required permanent pacemaker implantation. The rate of permanent pacemaker ranged from 2% to 51% in individual studies, with a median of 28% for the CV, and 6% for the ESV. Complete or high-grade heart block after TAVR is the most common indication for permanent pacemakers. The different rates of pacemaker implantation with CV versus ESV have been partly attributed to the different design (self-expanding vs. balloon expandable), sizes, and methods of deployment. The risk of permanent pacemaker implantation was 2.5-fold higher with CV than ESV. The CV also has a potential for deeper implantation in the LV outflow tract ( Fig. 14-19 ). This leads to more injury to AV node, His bundle, and/or the LBBs. The occurrence of AV block may be delayed caused by the self-expanding nature of the device.

Several studies have attempted to identify the predictors of conduction abnormalities and subsequent need for permanent pacemaker. Male sex, preexisting conduction abnormalities (first-degree AV block, RBBB, left anterior hemiblock), and intraprocedural AV block are predictors of the need for a permanent pacer post TAVR. According to current guidelines permanent pacemakers are recommended only for patients with symptomatic bradycardia and/or high degree AV block. However, studies have shown that new onset LBBB or QRS prolongation following TAVR are important and independent predictors of for all-cause mortality. In a prospective study of 50 consecutive patients undergoing TAVR with CV, pacemakers were prophylactically implanted in 17 patients with preexisting BBB or BBB occurring during TAVR. Ten of 17 patients (58.8%) developed episodes of high-degree AV block requiring dual-chamber pacing mode (DDD) (mode switch from SafeR). In five of the cases (29.4%) the first documented episode of high-degree AV block occurred after hospital discharge. Intensified monitoring may be reasonable in these patients treated with CV to assess the need for pacemaker. Rivard et al prospectively studied 75 patients undergoing TAVR with an electrophysiology study before and after TAVR. Eleven patients (14.7%) developed AV-block during the index hospitalization and three (4.0%) after hospital discharge over a median follow-up of 1.4 years. In multivariate analysis that considered all patients, the delta-HV (HV-interval after TAVR minus HV-interval before TAVR) of ≥13 msec was independently associated with AV-block. In the subgroup of patients with new-onset LBBB, the postprocedural HV-interval of ≥65 msec was strongly associated with AV-block.

Persistent heart block occurs infrequently (0.5% to 2% of patients) after radiofrequency catheter ablation (RFA) of septal accessory pathways, or the slow AV nodal pathway in patients with AV nodal reentrant tachycardia. Transient intraprocedural AV block during ablation performed close to the AV septum does not necessarily indicate that permanent pacemaker implantation is required. Ablation of the fast pathway in AV nodal reentrant tachycardia in the anterior septum is associated with a higher risk of transient AV block than RFA of the slow pathway in the posterior septum. In more than 500 patients, transient second- or third-degree AV block was seen in 20% during fast-pathway ablation, in 2.3% during slow-pathway ablation, and in 42% during combined fast-and-slow pathway attempted ablation. Within 7 days after RFA, however, persistent AV block was seen in 3.4%, 0.2%, and 0% of patients in these groups, respectively.

Late occurrence of unexpected heart block after RFA of AV nodal reentry (using a posterior approach) or posteroseptal accessory pathways is rare (<0.5% incidence) and often resolves after a few weeks. In patients who experience this rare RFA complication, prolonged clinical observation and monitoring rather than immediate pacemaker implantation is a reasonable approach. The risk for development of heart block is decreased with the use of cryoablation for the treatment of AV nodal reentry and accessory pathways near the AV node. A higher incidence of heart block (1% to 10% of patients) was observed when patients underwent surgical ablation for the WPW syndrome, especially when the accessory pathway was in an anteroseptal, intermediate septal, or posteroseptal location, or after surgical modification of the AV node for treatment of AV nodal reentrant tachycardia.

Radiofrequency catheter ablation is used to create permanent complete AV block in patients with paroxysmal and chronic atrial tachyarrhythmias (most frequently AF). This treatment option is reserved for the small group of patients in whom AV node–blocking drugs cannot control the heart rate, or who are intolerant, unwilling, or unable to take drugs to maintain sinus rhythm or control the ventricular response during AF. In most studies, RFA of the AV junction can be accomplished in more than 90% of patients with a right-sided approach through placement of an ablation catheter across the tricuspid valve and recording of a His bundle potential, or less frequently, by placement of the catheter in the left ventricle on the septum underneath the noncoronary cusp of the aortic valve to record a His bundle potential.

Radiofrequency ablation of the AV junction should be performed only in patients with a previously implanted permanent pacemaker, or at permanent pacemaker implantation (class I indication for pacing). There are no studies to assess outcome without permanent pacing after catheter RFA of the AV junction. Radiofrequency current ablation of the AV junction usually results in a junctional escape rhythm of 40 to 50 bpm. In one study, about 65% of patients had an escape rhythm with an average rate of 39 bpm, with a new RBBB in 24%, a new LBBB in 6%, and an idioventricular rhythm in 19%. In another study involving 96 patients, 79% had an escape rhythm immediately post AV nodal ablation. At 1 year, 88% of these patients had an escape rhythm. Several studies have shown AV junction ablation with pacemaker therapy to be highly effective at controlling symptoms and to result in improved quality of life in patients with paroxysmal and chronic AF. Long-term survival after “ablate and pace” approach has been reported by Ozcan and colleagues. Following 250 patients who underwent ablation from 1990 and 1998 at the Mayo Clinic, survival was compared with age- and sex-matched controls of the Minnesota population, and consecutive patients with AF who received drug therapy. During a mean of 36 ± 26 months of follow-up, 78 patients died, and when adjusted for underlying heart disease survival was similar to expected survival in the general population. In patients with depressed LV function, significant improvements in ventricular function are measured after ablation and pacing in 20% to 40% of patients in some series. Because of the deleterious effects and clinical outcomes of chronic RV pacing, investigators have evaluated the utility of biventricular pacing. Several trials have shown the efficacy in reducing heart failure clinical manifestations with CRT therapy compared with RV apical pacing.

AV nodal modification is a catheter ablation procedure designed to impair but not fully destroy AV nodal conduction in patients with rapid ventricular rates during AF. Radiofrequency energy is delivered in and around the slow AV nodal pathway in the posterior septum in an attempt to leave conduction intact over the fast AV nodal pathway. At present, however, AV nodal modification has fallen out of favor and is performed infrequently in patients with AF. In some patients AV nodal modification results in a slower ventricular response during AF and possibly avoids permanent pacemaker placement, but in other patients there is an unpredictable decrease in the ventricular rate. Patients who undergo AV nodal modification may remain symptomatic because of recurrent rapid AV conduction or the irregularity of the ventricular response during AF and may subsequently require complete AV nodal ablation. A bimodal R-R histogram during AF has been suggested as indicative of dual–AV nodal physiology, and may be a predictor of successful outcome after AV nodal modification. However, the risk of sudden death or syncope from unexpected, late CHB is a significant concern with this procedure. The rate of inadvertent AV block during the procedure may be as high as 25%. The incidence of long-term AV block is quite variable and also controversial, with estimates for late development of CHB ranging from 0% to more than 20% in different series.

In patients with blunt or penetrating chest trauma, a variety of conduction disturbances, including AV block, have been reported, but appear to be rare complications of this type of injury. The reported conduction abnormalities after chest trauma consist of BBB and varying degrees of AV block, including CHB. The most common abnormality is RBBB, followed by first-degree AV block, and the least common is CHB. Most AV conduction defects after traumatic chest injury are transient and resolve early. A few cases of persistent heart block requiring permanent pacemaker implantation have been described. Delayed development of complete AV block has been seen, occurring 15 to 30 days after injury, suggesting that patients with blunt chest trauma should be monitored for late complications. The severity of injury does not always correlate with the development of posttraumatic complications, including conduction disorders. The mechanism of conduction defects in this setting may be related to ischemia and infarction of the conduction system.

Complete heart block has been described in various infectious diseases, including bacterial, viral, fungal, protozoan, and rickettsial infections. Heart block may occur with endocarditis and may be either transient or permanent. In most infectious diseases, heart block is transient and resolves with treatment of the underlying infection. In some cases, transient heart block may recur, and permanent pacing is required. This is particularly true in patients with entities such as endocarditis, in which a valve ring abscess may erode into the conduction system, and in patients with infections such as Chagas disease. AV block occurs in up to 25% of patients with endocarditis complicated by perivalvular abscess, with the aortic valve involved much more than the mitral valve.

Lyme disease is the most common cause of reversible AV block in younger patients. This systemic illness, first described in 1975, was characterized later as an infection caused by a spirochete, Borrelia burgdorferi, which is transmitted to humans by a tick bite. This illness is often characterized by a rash, erythema chronicum migrans, which is followed by cardiac and neurologic abnormalities, and in some cases by arthritis. Cardiac involvement may occur in 8% to 10% of Lyme disease patients, is generally transient, and may consist of a myocarditis or a myopericarditis. Varying degrees of AV block are a common manifestation of carditis, occurring in about 75% of patients. More than 50% of patients with Lyme disease with AV block have symptomatic high-grade or complete AV block that requires temporary pacing. Most often the site of block is localized to the AV node, although occasional cases have been reported in which the site of block is intra-Hisian or infra-Hisian. Continuous cardiac monitoring is recommended in all patients with second-degree AV block and a prolonged P-R interval of more than 0.30 second because of the risk for development of complete AV block. CHB generally resolves within 1 to 2 weeks. Recurrent AV block has not been reported. Rarely, some patients may have symptomatic AV block as the sole manifestation of Lyme disease. Permanent pacing is rarely required except for persistent CHB, which is uncommon. Two important axioms worth repeating are that (1) heart block associated with infectious disease usually resolves with appropriate and prompt antibiotic treatment and (2) conduction disease is rarely the only manifesting feature of an infectious illness.

Heart block may occur rarely after radiation therapy or chemotherapy. Heart block may occur after radiation therapy if radiation is directed at the mediastinum, as for Hodgkin and some non-Hodgkin lymphomas. Radiation therapy may induce fibrosis of the cardiac conduction system, in addition to the atrial and ventricular myocardium, and may accelerate coronary atherosclerosis. Rarely, tumors, including mesothelioma of the AV node, cardiac lymphoma, and metastatic disease to the heart from breast, lung, or skin cancer, may involve the conduction system. AV block has been reported as a rare complication of chemotherapeutic agents (e.g., arsenic trioxide treatment for leukemia). In general, it is unusual for toxicity to antineoplastic drugs such as doxorubicin to result in damage to the cardiac conduction system.

Certain neuromuscular diseases may give rise to progressive and insidiously developing cardiac conduction system disease. The disorders include Duchenne muscular dystrophy, fascioscapulohumeral muscular dystrophy, X-linked muscular dystrophy, myasthenia gravis, myotonic dystrophy, and Friedreich ataxia. Abnormalities of conduction manifest as infranodal conduction disturbances resulting in fascicular block or CHB. This has been noted particularly in Kearns-Sayre syndrome (progressive external ophthalmoplegia with pigmentary retinopathy), Guillain-Barré syndrome, myotonic muscular dystrophy, slowly progressive X-linked Becker muscular dystrophy, and fascioscapulohumeral muscular dystrophy. Myotonic muscular dystrophy and Kearns-Sayre syndrome are both associated with a high incidence of conduction system disease that frequently is rapidly progressive and cannot be predicted by the ECG or isolated His bundle recordings. His-Purkinje disease can culminate in fatal Stokes-Adams attacks unless anticipated by insertion of a pacemaker. In a study of 49 patients with myotonic dystrophy (46 ± 9 years old) and an H-V interval of 70 msec or longer, high-grade paroxysmal AV block was recorded after pacemaker implantation in 47% of patients who had had no known bradycardia on entry into the study. The researchers concluded that prophylactic implantation of permanent pacing should be considered in patients with myotonic dystrophy and prolonged H-V interval (≥70 msec) even without bradycardia-related symptoms. Waiting for the development of complete AV block in patients with neuromuscular diseases may expose them to significant risk of sudden death or syncope related to AV block. Permanent pacing should be considered early in the course of neuromuscular disease and should be offered to the asymptomatic patient once any conduction abnormality is noted. A recent study found that “severe” ECG abnormalities (rhythm other than sinus, QRS >120 msec, P-R interval >240 msec, or second- or third-degree AV block), and clinical diagnosis of atrial tachyarrhythmia are independent predictors, along with moderate sensitivity, of sudden death in patients with myotonic dystrophy type 1.

Heart block may occur with amyloid and other infiltrative diseases, including hemochromatosis, porphyria, oxalosis, Refsum disease, carcinoid, Hand-Schüller-Christian disease, and sarcoidosis.

Cardiac sarcoidosis should be considered in the differential diagnosis of a young patient (20 to 40 years old) presenting with CHB. Cardiac manifestations of sarcoidosis are present in at least 25% of patients with systemic sarcoidosis, and can include Mobitz II, second-degree AV block, LBBB, RBBB or CHB (~30%), ventricular tachyarrhythmias, intracardiac masses, ventricular aneurysms, and dilated cardiomyopathy. Current expert consensus statement on arrhythmias associated with cardiac sarcoidosis recommend that in patients aged younger than 60 years presenting with unexplained Mobitz II second-degree AV block or CHB, further evaluation with high resolution chest CT and/or cardiac MRI may be necessary to diagnose cardiac sarcoidosis. However, only 40% to 50% of patients with cardiac sarcoidosis at autopsy had clinical evidence of myocardial involvement during their lifetime. Newer modalities such as magnetic resonance imaging (MRI) may be helpful in the diagnosis of cardiac sarcoid, which can be difficult because of the lack of definitive criteria and the nonspecific clinical manifestations. Cardiac sarcoidosis is associated with noncaseating granulomas that tend to involve the conduction system with varying degrees of AV conduction block. The majority of patients with sarcoid heart disease have extracardiac involvement that manifests either clinically or on biopsy. Other organ systems involved in sarcoid include the lymph nodes, skin, eyes, and the nervous, musculoskeletal, renal, and endocrine systems. Isolated cardiac involvement in sarcoidosis is less common and usually precedes future systemic sarcoidosis. In a recent retrospective study of 133 patients aged 18 to 55 years with second- or third-degree AV block receiving permanent pacemakers, 72 patients had unexplained AV block. Biopsy verified cardiac sarcoidosis (CS), or giant cell myocarditis (GCM) was found in 14 (19%), and 4 (6%) respectively. The prevalence of CS or GCM in patients younger than 55 years of age with initially unexplained AV block was as high as 25%. Although there are no large randomized trials or prospective registries of patients with cardiac sarcoidosis, the available literature indicates that cardiac sarcoidosis with heart block, ventricular arrhythmias, or LV dysfunction is associated with a poor prognosis and an increased risk of sudden death. Myocardial involvement in sarcoid accounts for up to 13% to 25% of deaths from sarcoidosis. In Japan, sarcoid heart disease is more common, accounting for up to 85% of mortality from sarcoidosis. AV block may resolve after long-term treatment with corticosteroids, alone or in combination with other immunosuppressive therapy. However, heart block in patients with sarcoid heart disease generally warrants a permanent pacemaker because of possible disease progression, even if AV conduction block reverses transiently. An ICD should be considered in patients with sarcoidosis undergoing device implantation for AV block because of the risk of ventricular tachyarrhythmias and sudden death (class IIa recommendation). However, definitive clinical data are not available to stratify risk of sudden cardiac death among patients with cardiac sarcoidosis. Thus decisions regarding ICD implantation must be individualized. Recommendations regarding management are summarized by the recently published sarcoidosis guidelines.

Connective tissue disorders giving rise to conduction system disease include periarteritis nodosa, rheumatoid arthritis, polymyositis, mixed connective tissue disorders, Reiter syndrome, ulcerative colitis, scleroderma, Takayasu arteritis, systemic lupus erythematosus, and ankylosing spondylitis. In one study of 50 consecutive patients with scleroderma, EPS demonstrated conduction abnormalities in up to 50% of patients, suggesting a much higher level of cardiac involvement in patients than readily apparent clinically. However, CHB is uncommon. Most patients with AV conduction disorders have other clinical manifestations of the connective tissue disease. AV block has been reported as a rare complication of antimalarial therapy used to treat systemic autoimmune diseases (e.g., chloroquine for rheumatoid arthritis or systemic lupus erythematosus).

Anti-Sjögren syndrome-related antigen A (Anti SSA/Ro)-associated AV block has been described in adults. Although it is well recognized that anti-Ro/SSA autoantibodies have an immunopathologic potential toward the fetal conduction system, it is traditionally believed that the adult heart is invulnerable to these autoantibodies. Currently available data suggests two possible forms of anti-Ro/SSA-associated AV block in adults: (1) an acquired form and (2) a late progressive congenital form. The acquired form is characterized by the presence of anti-Ro/SSA autoantibodies in the affected subject, and the conduction defect seems related to direct autoantibody-mediated electrophysiologic inhibition of calcium channels on cardiomyocytes. In these patients immunosuppressive therapy (methylprednisolone + azathioprine) may normalize rhythm disturbances. In contrast, in late progressive congenital form, anti-Ro/SSA autoantibodies are not detectable in the subjects, whereas their mothers are seropositive. In these patients prenatally established structural damage of immune origin appears to be the pathologic basis. Immunosuppressive therapy has no clinical value in these patients. It is estimated that these two forms may represent at least 20% of all cases of isolated CHB of unknown origin in adults (10% of each form).

Exercise-induced transient AV block is a relatively rare condition that is usually caused by a block in the His-Purkinje system ( Fig. 14-20 ). The incidence of exercise-induced AV block during treadmill exercise testing is between 0.1% and 0.5%. Donzeau et al reported 14 symptomatic patients with exercise-induced AV block, in 9 of whom block was localized to an infranodal site. Other studies have confirmed that exercise-induced AV block is primarily infra-Hisian. In these studies, about 25% to 75% of patients had underlying BBB. Several reports of patients with cardiac asystole after exertion have demonstrated postexercise sinus arrest with ventricular asystole. Some researchers proposed that transient ischemia of the conduction system is a mechanism of exercise-induced AV block in patients with severe RCA lesions and chronic infranodal conduction disturbances. A case of pseudo-AV block during exercise was caused by His bundle parasystole. Permanent pacing is recommended in patients with exercise-induced AV block, even in the asymptomatic state, because of the high incidence of symptomatic AV block.

Drug-induced bradycardia is a common and important clinical problem. Many common drugs, including β-adrenergic blockers, calcium channel antagonists, digoxin, class I and III antiarrhythmic drugs, tricyclic antidepressants, phenothiazines, lithium, and donepezil (a cholinesterase inhibitor used to treat Alzheimer disease), can cause AV conduction disturbances. In patients presenting with drug-induced AV block, drug therapy can be stopped entirely, reduced in dosage, or continued if there is no acceptable alternative. In the last case, if drug-induced AV block results in symptomatic bradycardia, permanent pacemaker implantation is recommended (class I indication). On the other hand, if the AV block is caused by drug toxicity, is expected to resolve, and is unlikely to recur, pacemaker implantation is generally considered unnecessary according to current guidelines. However, if AV block occurs in the setting of drug use or toxicity, and the block is expected to recur even after the drug is withdrawn, pacemaker implantation may be considered (class IIb indication).

Supporting this guideline recommendation, Zeltser et al suggest that in the majority of patients presenting with presumed drug-induced AV block, discontinuation of the offending medications does not obviate the need for pacemaker implantation. In this study, AV block persisted after drug discontinuation in most patients. Furthermore, even if AV block resolved when the drugs were discontinued, patients remained at risk of recurrent AV block in the absence of offending drugs. Among a consecutive series of 169 mostly elderly patients with structural heart disease and symptoms of second- or third-degree AV block not related to AMI, vasovagal syncope, digitalis toxicity, or RFA, 92 patients (54%) had drug-induced AV block while receiving β-blockers, and/or verapamil, or diltiazem. Drug therapy was discontinued in 79 patients; in 32 (41%), AV block resolved within 48 hours. However, in 18 (56%) of the 32 patients with drug-induced AV block who experienced spontaneous resolution of AV block after drug discontinuation, AV block recurred. Ten of these patients had syncope during the subsequent 3 weeks of follow-up without drug therapy. On the basis of this experience, the researchers estimated that the medications caused only 8% of all cases of AV block and only 15% of occurrences of AV block in patients receiving medications. In a recent study involving 108 patients using AV blockers presenting with symptomatic AV block without myocardial infarction, electrolyte abnormalities, digitalis toxicity, and vasovagal syncope, drug discontinuation was associated with resolution of AV block in 72% of cases. However, 27% of patients with improved AV conduction experienced a recurrence of AV block despite withdrawal of the culprit drug. Roughly half of the patients with drug-induced AV block underwent permanent pacemaker implantation.

Vagally mediated AV block infrequently requires a permanent pacemaker, especially in the absence of recurrent syncope or profound asystole. AV block may occur in the setting of increased vagal tone in response to various stimuli such as carotid sinus hypersensitivity, coughing, swallowing, and visceral distention. Because vagally mediated AV block often occurs in young, otherwise healthy patients, especially during sleep, it must be differentiated from type II second-degree AV block, because the latter patients require implantation of a permanent pacemaker. In most cases, vagally induced AV block occurs at the level of the AV node, and is associated with a narrow QRS complex. As a general rule, vagally mediated AV nodal block shows obvious heart rate slowing, even if only slight, before the onset of block, because of the concomitant effect of increased vagal tone on the sinus node ( Fig. 14-21 ). Rarely, vagal stimulation may precipitate phase IV or bradycardia-mediated block in the His-Purkinje system.

Atrioventricular Block Without Bundle Branch Block

In a series of 684 consecutive patients with AMI admitted to the Los Angeles County-University of Southern California Medical Center (LAC-USCMC) Coronary Care Unit (CCU) between 1966 and 1970, 110 had AV block (16%); 79 of 110 patients (72%) with AV block did not have BBB. The total percentages of patients who had first-, second-, or third-degree AV block at some time were 6%, 7%, and 4%, respectively ( Table 14-6 ). AV block is more often associated with inferior infarction; and in those who experience second- and third-degree blocks, inferior AMI is present two to four times more frequently than anterior AMI. The site of block in inferior infarction is above the His bundle in about 90% of patients, whereas in anterior infarction, the conduction abnormality is usually localized below the node at the His bundle and the distal conducting system ( Table 14-7 ). In patients with inferior AMI, progression of AV block typically occurs in stages; whereas in those with anterior AMI, it may occur in stages, or third-degree AV block, or ventricular asystole may develop suddenly ( Fig. 14-22 ).

AV block complicating AMI is associated with a high mortality rate (24% to 48%), two to three times that for AMI without AV block (9% to 16%). Even with thrombolytic therapy and primary percutaneous coronary interventions, if AV block occurs in the setting of AMI, mortality remains high, especially in anterior MI. The poor prognosis generally reflects the larger ischemic/infarcted region associated with development of AV block in the setting of AMI. Although AV block that occurs during inferior AMI predicts a higher risk of in-hospital death, it may be less predictive of long-term mortality in patients who survive to hospital discharge. The major cause of death in patients who have AV block in the setting of AMI is pump failure. Death is related primarily to extensive myocardial damage, but in an important minority of patients, it can be attributed to sudden ventricular asystole or severe bradycardia.

Atrioventricular Block with Bundle Branch Block

Before the widespread use of thrombolytic therapy, BBB was present during hospitalization in 8% to 18% of patients with AMI. The presence of a persistent intraventricular conduction defect during the hospitalization increases the risk of high-grade AV block in addition to other complications and is associated with poor survival in patients with AMI. In patients receiving thrombolytic therapy, the incidence of persistent intraventricular conduction defects appearing during the hospitalization is reduced to about 4% to 9%. However, the adverse risk associated with intraventricular conduction defects (except for isolated left anterior hemiblock) has persisted even in the modern era of AMI reperfusion therapy.

In an older series of 2779 patients with AMI admitted from 1966 to 1977 to the LAC-USCMC CCU, 257 (9%) had BBB ( Table 14-8 ). The conduction abnormality was “new” in 60%. When the site of infarction was not obscured by the BBB in the LAC-USCMC series, the block was associated with anterior AMI about three times as often as with inferior AMI. Progression of AV block occurred in 75 of the 257 patients (29%) with AMI and BBB (see Table 14-8 ).

There were 37 patients with third-degree AV block and BBB, 13 (35%) of whom were admitted in third-degree block. Of the 24 who progressed to third-degree block, 11 (46%) had demonstrated second-degree block; 7 of the 11 had type II second-degree block. Consistent with the LAC-USCMC series, AV block occurred in other studies in about one third of patients with AMI and BBB.

In the multicenter, retrospective study reported by Hindman et al high-grade AV block (third- or second-degree block with a type II pattern) occurred in 55 of 432 patients (22%). In the LAC-USCMC study, high-grade AV block occurred in 46 of 257 patients (18%). To determine which patients were at considerable risk for development of high-grade AV block while hospitalized with AMI, several variables were analyzed. Despite some differences in the findings between the two studies, both studies found that the following subgroups of patients were at highest risk for high-grade AV block: (1) those with new bilateral BBB plus first-degree AV block (risks, 38% and 43% ), (2) those with bilateral BBB plus first-degree AV block (risks, 20% and 50%, respectively), and (3) those with new BBB plus first-degree AV block (risks, 19% and 29%, respectively). Subgroups in whom the findings of the two studies show different risks can be considered to be at moderate risk for high-grade AV block. These subgroups include patients with (1) new bilateral BBB (risks, 31% and 15%, respectively) ( Fig. 14-23 ), (2) first-degree AV block (risks, 13% and 30%, respectively), and (3) bilateral BBB (risks, 10% and 18%, respectively). The remaining subgroups of patients with AMI and BBB can be considered to be at lowest risk (≤10%) for development of high-grade AV block. The database assembled by the Multicenter Investigation of the Limitation of Infarct Size (MILIS) was used to develop a simplified method of predicting the occurrence of CHB. It must be recognized that the algorithms and clinical databases used to estimate the risk for occurrence of CHB in the setting of AMI were developed in the prethrombolytic era, and thus must be interpreted cautiously when applied to the modern post-AMI patient population.

The short-term and long-term mortality and sudden death rates are higher in patients with AMI and BBB (25% to 50%) than in those without BBB (15%). The one exception is the isolated finding of left anterior fascicular block in patients with AMI, which appears not to carry an unfavorable prognosis. When the infarction is extensive and produces diffuse conduction system abnormalities progressing to high-grade AV block, it is also extensive enough to damage a large amount of myocardial muscle. Therefore affected patients often die from pump failure and from ventricular tachyarrhythmias. In some patients, sudden third-degree AV block or asystole is abrupt and fatal if untreated.

Impact of Reperfusion

Several prospective trials involving thrombolytic therapy of AMI provide data pertaining to the effect of such therapy on the development of high-grade (second- or third-degree) AV block and BBB.

Clemmensen et al examined the effect of thrombolytic therapy and adjunctive angioplasty as a treatment strategy for AMI (TAMI trial) after inferior AMI. In all patients, treatment was initiated with thrombolytic agents within 6 hours of symptom onset. There were 373 patients with an inferior AMI, of whom 50 (13%) had complete AV block; 54% of these patients had complete AV block on admission. In all but two patients, the block was manifest within 72 hours of onset of symptoms. There was no difference in the rate of infarct vessel patency between those with and those without AV block (90% and 91%, respectively). A precipitating clinical event—vessel reperfusion, performance of percutaneous transluminal coronary angioplasty (PTCA)—or vessel reocclusion was identifiable in 38% of cases of complete AV block. At the predischarge angiogram, the vessel patency rate was 11% lower in the group with AV block than in the group without block (71% vs. 82%, respectively). Those in whom AV block developed showed a decrease in LVEF between the early postthrombolytic angiogram and the predischarge angiogram. Also, those who experienced AV block had higher in-hospital mortality, 10 of 50 (20%) versus 12 of 323 (4%; P < 0.001). When age, LVEF in the acute phase, number of diseased vessels, and grade of blood flow through the culprit lesion were entered into a multivariate model, the development of complete AV block still contributed significantly to the risk for in-hospital death. After a median follow-up period of 22 months, mortality rates for patients with and without AV block were equivalent (2%). These data suggest that compared with the prethrombolytic era, use of thrombolytics and angioplasty has altered neither the incidence of complete AV block nor the associated greater ventricular dysfunction or in-hospital mortality of patients with inferior AMI.

In another study of 1786 patients with inferior AMI who received recombinant tissue-type plasminogen activator (rt-PA) within 4 hours of symptom onset, high-grade (second- or third-degree) AV block developed in 214 (12%) (TIMI-II trial). Of the group who had AV block, 113 (6.3% of total, or 52% of those who ever had AV block) had this finding on admission. The remaining 101 patients (5.7%) experienced heart block during the 24 hours after treatment with thrombolytics. Patients who already had high-grade AV block before receiving thrombolytic therapy tended to be older and had a higher prevalence of cardiogenic shock than those without heart block. Nevertheless, the presence of heart block did not carry a higher 21-day mortality rate independent of other variables such as shock, and the 1-year mortality rate was similar to that in the group without heart block. Patients in this study were randomly assigned to coronary arteriography 18 to 48 hours after admission. Among those who had heart block after admission, the infarct-related artery was less frequently patent than in those without heart block (28 of 39 [72%] vs. 611 of 723 [84.5%]; P = 0.04]). The RCA was the infarct-related artery more often in patients who had heart block than in those who did not (36 of 69 [92.3%] vs. 542 of 723 [75.1%], respectively; P = 0.04). Among patients without heart block at hospital admission, death occurred within 48 hours in 4 of 9 patients (44%) with new heart block, and in 8 of 68 (12%) without new heart block at 24 hours. The 21-day mortality rate was higher in the group with AV block than in the group without block (10 of 101 [9.9%] vs. 35 of 1572 [2.2%], respectively; P < 0.001), as was the 1-year mortality rate (15 of 101 [14.9%] vs. 65 of 1572 [4.2%], respectively; P = 0.001). A temporary pacemaker was inserted in about one third of patients who had heart block on admission and in almost 30% of patients who experienced heart block after institution of thrombolytic therapy, whereas only 6.5% of patients without heart block received temporary pacemakers. None of the patients who had heart block on admission or who experienced heart block later received permanent pacemakers, but four patients without heart block at 24 hours went on to receive permanent pacemakers. Heart block was not listed as a primary or contributing cause of death in any patient.

The data from these two studies of thrombolytic therapy suggest that aggressive treatment with thrombolytic agents or thrombolytic therapy plus angioplasty is not associated with a lower incidence of high-grade or complete AV block in patients with inferior AMI than was seen in the prethrombolytic era; the incidence remains about 10% to 13%, with about one half of cases appearing as new AV block during hospitalization. The infarct-related vessel is more often the RCA, and there is a lower vessel patency rate after thrombolysis among patients in whom AV block complicates inferior AMI. In-hospital and early posthospitalization mortality rates are higher in patients with block than in those without AV block, among patients treated with thrombolytics, with or without angioplasty. It has not been clear that patients with acute AV block continue to be at greater risk of death over the long term if they survive the initial hospitalization. A study that pooled data from four large RCTs involving 70,000 patients with AMI treated with thrombolytic therapy evaluated the short- and long-term mortality rates associated with second- and third-degree AV blocks. Compared with patients with AMI and no AV block, patients with AMI and AV block were more than three times more likely to die within 30 days and 1.5 times more likely to die during 1 year of follow-up. The higher short- and long-term mortality rates were observed in the setting of inferior and anterior AMI ( Fig. 14-24 ). The presumption remains, as before the era of thrombolytic therapy, that the presence or development of AV block is associated with a higher mortality because it tends to indicate the presence of more extensive infarction or injury.

In the last decade, most patients with acute MI are treated with primary percutaneous intervention (PCI) rather than thrombolysis. There is significant paucity of data regarding AV block during acute MI in the primary PCI era. A recent retrospective Danish study showed significantly lower incidence ( n = 67; 3.2%) of second- or third-degree AV block in 2073 acute ST elevation MI patients treated with primary PCI. The incidence of late event occurring after 48 hours was only 9% compared with rates of up to 20% in the thrombolytic studies. The incidence of AV block was 7% in RCA infarcts compared with 1% in LAD infarcts. In this study, only 6 of the 67 (9%) patients who developed AV block required implantation of permanent pacemaker before discharge suggesting the transient nature of AV block in this setting. Within 30 days after acute MI, the probability of death was 33% in the AV block group versus 5% in the nonAV block patients. However, the landmark analysis of survival in patients alive at 30 days post MI, the rate of mortality was similar in the two groups. In a prospective registry (Korea AMI registry) involving 13,682 patients with AMI (unclear percentage of patients with ST elevation), the incidence of second- or third-degree AV block at presentation was 2.7%. PCI with drug eluting stents were performed in 89.8% of patients. Patients with heart block showed worse clinical parameters at initial admission, and the presence of heart block was associated with a 30-day major adverse cardiac events (MACE) (death, nonfatal MI or revascularization) rate of 16.7% compared with 8% in patients without heart block in univariate analyses ( P < 0.001). However, the prognostic impact of heart block was not significant after adjustment of potential confounders ( P = 0.489). Among patients with heart block, patients with a culprit in the LAD had worse clinical outcomes than those of patients with a culprit in the LCx or RCA. The current strategy of primary PCI for acute ST elevation MI appears to have significantly reduced the incidence of high grade AV block. Nevertheless, patients who develop AV block are at higher risk foracute mortality.

In trials conducted with thrombolytic therapy in AMI, BBB is reported present on admission in up to 2% to 4% of patients. In the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial, among 26,003 North American patients, 420 (1.6%) had left ( n = 131) or right ( n = 289) BBB on admission ECG. Interestingly, reversion of BBB occurred in 24% of patients during hospitalization and was associated with a 50% relative risk reduction in 30-day mortality, from 20% to 10%. Prognosis for patients who recovered normal intraventricular conduction (i.e., transient BBB) was similar to that for patients who never had BBB. In a multicenter prospective study of 1238 patients with 1-year follow-up, a higher rate of new and transient RBBB and lower rate of bifascicular block was found in patients receiving thrombolytic therapy. The overall prognostic implications of RBBB were unchanged and included a higher rate of heart failure, greater chance of needing a permanent pacemaker, and a higher 1-year mortality rate.

Bundle Branch Block after Recovery

The subset of patients with persistent BBB and transient high-grade AV block during AMI are at increased risk of late mortality. It is now recognized that most of these deaths are sudden and result from ventricular tachyarrhythmias. In a previous era, controversy surrounded whether these patients were at high risk for sudden death from a bradyarrhythmia. Some investigators suggested that patients with persistent BBB plus transient AV block during the acute infarction had a higher risk of dying suddenly as a result of CHB. Most of the older studies were limited by the small number of patients with AMI enrolled and monitored and may not be applicable to the current era of post-AMI management. Despite the controversy regarding whether late sudden death in patients with BBB is caused by heart block, permanent ventricular pacing is indicated for transient advanced second- or third-degree infranodal AV block and associated BBB after AMI, according to current practice guidelines (class I indication).

Electrophysiologic Studies in Atrioventricular Block and Bundle Branch Block

Electrophysiologic studies with recording of the His bundle electrogram (HBE) are not performed routinely at present for risk stratification of patients with AV block after AMI. HBE studies after AMI were used primarily in the 1970s and 1980s to identify the sites of AV conduction disturbances, which were shown to be either in the AV node (proximal block) or in the distal conduction system (distal block). The presence of distal block identifies patients at high risk for development of high-grade AV block. In individual cases in which the diagnosis is uncertain (e.g., type I second-degree AV block in patients with BBB) or infranodal or multilevel block is suspected, EPS is helpful in identifying the sites of AV block ( Fig. 14-25 ).

In patients with inferior AMI, the site of AV block is usually proximal. Harper et al showed that 30 of 32 patients (94%) with inferior AMI and third-degree AV block had AV nodal block during HBE; the remaining two patients were in normal sinus rhythm during the study and had a normal P-R interval and normal A-H and H-V intervals. In this group of patients, hospital mortality was low (13%) and HBE offered no advantage.

In anterior AMI, the block is frequently in the distal conduction system. In the study by Harper et al, 50% of patients (9 of 18) with BBB and a normal P-R interval on ECG had a prolonged H-V interval, but there were no hospital deaths in this group. Of the 22 patients who experienced AV block and BBB, 5 had proximal block, 14 had distal block, and 3 had both proximal and distal blocks. Thus in both groups of patients, HBE was the only means of localizing the block in the proximal or distal portion of the conduction system. Hospital mortality in the patients who progressed to second- or third-degree AV block was higher (9 of 12 patients, 75%) than in those who remained in first-degree AV block (2 of 10 patients, 20%). Despite the fact that a prolonged H-V interval could identify a group of patients who may be at high risk for high-grade AV block, several studies have shown that it does not help in assessing the short- or long-term prognosis of patients after AMI.

Indications for Pacing