Atrioventricular Block

Treatment and prognosis of atrioventricular (AV) block depends on the exact location, either intranodal or infranodal. Besides invasive electrophysiological measurements, several noninvasive methods are used to identify the site of conduction block.

The AV node and the His-Purkinje system are innervated differently by the autonomic nervous system, with the AV node being highly innervated by sympathetic and parasympathetic nerves and the His-Purkinje system being poorly innervated.¹ These differences are the basis of provocative maneuvers to determine further the exact location of an AV block.

Carotid sinus massage increases vagal tone and worsens AV nodal block.² Isoproterenol, exercise, and atropine are known to increase sympathetic tone, improving AV nodal conduction.² Because of these changes on rate impulse conduction through the AV node, these maneuvers exert different effects on infranodal block; for example, after carotid sinus massage, the sinus rate drops, and therefore the presence of a functional infranodal block can disappear, depending on whether a lower impulse rate approaches the infranodal conduction system, re-establishing 1 : 1 conduction. However, increasing the impulse rate (e.g., by atropine) could worsen the functional infranodal block. So in regard to infranodal block, carotid sinus massage improves infranodal block, and exercise and atropine worsen infranodal block.

Some authors have tried to evaluate the role of adenosine or its precursor adenosine 5′-triphosphate (ATP) to diagnose high-degree AV block as the underlying mechanism for unexplained syncope.³ Adenosine binds to the A1-receptor, thus exerting its effects of depressing sinus node automaticity, slowing or blocking AV node conduction, and shortening and hyperpolarizing the atrial action potential as well as decreasing automaticity in Purkinje fibers.^4,5

Brignole et al suggested that an ATP test could be valuable for diagnosis of paroxysmal AV block based on a potentially higher ATP susceptibility of patients with syncope.⁶ However, the same group published data showing that ATP could predict AV block only in a few patients.⁷ Another study by Fragakis et al investigating adenosine in the context of sick sinus syndrome and unexplained syncope failed to demonstrate a valuable role for adenosine in confirming AV block as a cause of syncope as well.⁸ As a result, the usefulness of adenosine in detecting AV block has not been established.

During invasive EPS, the class I antiarrhythmic drug ajmaline can be used to unmask infra-Hisian conduction abnormalities.² A dose of 1 mg/kg is used in patients with normal systolic function. If the infra-Hisian conduction is pathologic, a second- or third-degree infra-Hisian block or an H-V interval greater than 120 ms occurs a few minutes after ajmaline infusion. Theoretically, ajmaline could be replaced by other class I antiarrhythmic drugs such as flecainide or procainamide, but the elimination half-life of ajmaline is shorter, which is an advantage for its use in a screening test.

Syncope

Carotid sinus hypersensitivity can be the underlying disease leading to syncope caused by a sinus pause. It can easily be tested for by performing carotid sinus massage over the region of carotid bifurcation (i.e., the maximal point of carotid pulsation between the angle of the mandible and the superior border of the thyroid cartilage) under continuous ECG and blood pressure monitoring for 5 seconds on both sides, one after another, in the supine, 70-degree, head-up tilt position.⁹ The test result is assumed to be positive if a sinus pause greater than 3 seconds (cardio-inhibitory subtype), a decrease of systolic blood pressure greater than 50 mm Hg (vasodepressor subtype), or both are observed. However, such sinus pauses can be observed in healthy individuals as well, so carotid sinus massage cannot definitively distinguish healthy individuals from sick individuals.^10,11

Tilt-table testing (TTT) is a widely used provocative test method for the assessment of syncope. Several protocols have been developed, with the Bruce protocol being the most widely used (see Chapters 48 and 70). In addition, isoproterenol or nitrates are used as provocative agents to increase the sensitivity and decrease the specificity of the TTT.²

ATP can be used for the evaluation of cardio-inhibitory syncope.¹³ According to a protocol developed by Flammang and colleagues, a rapid bolus of 20 mg ATP is administered. The ATP test result is considered positive if complete AV block greater than 10 seconds occurs or if the longest R-R interval after ATP administration is greater than 6 seconds.^14,15 Head-up TTT and the ATP test do not correlate well, which has led to the hypothesis that the ATP test reveals a form of syncope different from that detected by the head-up TTT or carotid sinus massage.^7,16 The ATP test is not routinely used; additional clinical trials are needed. According to the guidelines published by the European Society of Cardiology, the adenosine test is a class IIb recommendation because of its low predictive value.¹⁷

Sick Sinus Syndrome or Sinus Node Dysfunction

Sick sinus syndrome is a clinically heterogeneous disease. Underlying pathophysiological mechanisms include changes in intrinsic sinus node properties, sinoatrial (SA) conduction properties, and extrinsic factors such as autonomic regulation.¹⁸ To distinguish endogenous sinus node dysfunction from autonomic dysregulation responsible for sick sinus syndrome, intrinsic heart rate (IHR) can be determined with propranolol and atropine.¹⁹ With the patient under continuous ECG monitoring, 0.2 mg/kg propranolol is administered at 1 mg/min, followed by a single bolus of 0.04 mg/kg atropine over 2 minutes. IHR is determined as the maximum sinus rate after injection of atropine. Based on the formula IHR = 118.1 – (0.57 × Age), normal IHR is assumed to be within ±14% of the 95% confidence interval (CI) for age 45 years or younger or within ±18% for age 45 years or older. An abnormal IHR therefore represents dysfunction of intrinsic sinus node properties. In contrast, autonomically mediated sick sinus syndrome shows a normal IHR after autonomic blockade. By eliminating (para)sympathetic activity, propranolol or atropine testing facilitates discrimination of intrinsic sinus node dysfunction and autonomic dysregulation. Further evaluation of intrinsic sinus node dysfunction can be achieved by determining sinus node recovery time (SNRT) and SA conduction time (SACT) during EPS (see Chapter 39).

Fragakis et al evaluated the diagnostic value of adenosine in detecting sick sinus syndrome in a study with 19 patients, 12 of whom were control patients and 7 with syncope of unknown origin.⁸ The investigators measured the maximum corrected SNRT after atrial overdrive pacing at different cycle lengths and compared it with the longest sinus pause after adenosine administration corrected to basic cycle length. With a bolus of 0.15 mg/kg adenosine, they showed that this noninvasive test is at least comparable with the measurement of corrected SNRT in diagnosing sick sinus syndrome. However, they could not show any value for the use of adenosine in the diagnosis of AV block.

Another study by Burnett et al investigated adenosine as a provocative agent in 10 patients with sick sinus syndrome. By validating their results with EPS, they demonstrated that the lengthening of the sinus cycle length corrected to the basic cycle length after adenosine infusion offers a sensitivity of 80% and a specificity of 97% for the diagnosis of sick sinus syndrome.²⁰

The adenosine test may therefore be a suitable alternative in the diagnosis of sick sinus syndrome; however, because of the small number of patients enrolled in these studies, additional investigations are still necessary to assess the value of adenosine in the diagnosis of sick sinus syndrome.

Furthermore, administration of ajmaline has been shown to increase the sensitivity of EPS in the detection of sick sinus syndrome.² The test result is assumed to be positive if the corrected sinus node time is greater than 550 ms after ajmaline infusion.

Chronotropic Incompetence

Athletes often show resting bradycardia, but they can increase their heart rate adequately with exercise. In contrast, patients with chronotropic incompetence or sinus node dysfunction and resting bradycardia cannot appropriately accelerate their heart rate. A physical exercise stress test can be useful in differentiating nonpathologic bradycardia at rest from chronotropic incompetence. In addition, drug testing can be performed by increasing the heart rate after infusion of isoproterenol and atropine based on the sympathetic stimulation and parasympathetic blockade, respectively. Vavetsi et al studied 100 patients with sinus bradycardia but no obvious cardiac disease.²¹ According to their protocol, 2 mg atropine was injected, followed by incremental isoproterenol infusion starting at a dose of 2.4 mg/min up to a maximum of 7.2 mg/min (2 to 3 minutes and 1.2 mg/min isoproterenol per step). By measuring the maximum heart rate, they defined the chronotropic reserve. As a result, they clearly identified patients with deficient chronotropic response who required pacemaker implantation.

Atrioventricular Nodal Re-entrant Tachycardia and Atrioventricular Re-entrant Tachycardia

Dual conduction properties (fast and slow) exist in the AV node as the basis of AV nodal re-entrant tachycardia (AVNRT).²² Adenosine is routinely used to terminate AVNRT.⁴ However, AVNRT is a paroxysmal SVT that often self-terminates before ECG documentation can be performed. Thus patients with palpitations and tachycardia often remain undiagnosed and do not receive adequate therapy (e.g., ablation). In these cases, adenosine can be used for diagnostic purposes because the two pathways may respond differently to adenosine. A higher dose is necessary to block conduction in the slow pathway compared with the fast pathway, resulting in an abrupt increase in A-H and P-Q intervals detectable in intracardiac or surface ECG recordings, respectively.^23,24

With the patient under continuous ECG monitoring, adenosine is administered during sinus rhythm as a bolus of 6 mg (followed by a bolus of 0.9% saline) with additional 6-mg doses to a maximum of 18 mg or until second- or third-degree AV block occurs.^4,25 Some authors suggest a starting dose of 3 mg adenosine followed by further 3-mg steps or a dose regimen based on body weight, starting at 0.05 mg/kg with further application of 0.05 mg/kg.^4,24 In general, dose reduction should be considered in patients with concomitant dipyridamole therapy or those with heart transplants because of the increased effect of adenosine in these patients.⁴ Dual AV node physiology is considered if a sudden increase greater than 50 ms of the P-Q interval is seen, AV nodal echo beats occur, or AVNRT develops.

Tebbenjohanns et al used adenosine in 37 patients with symptoms of paroxysmal tachycardia but without ECG documentation who underwent EPS.²⁴ They used an average adenosine dose of 10.3 ± 4.2 mg and identified a sudden increase in the P-Q interval on the surface ECG in 76% of the patients with inducible AVNRT but in only 5% of the patients without AVNRT. Thus the adenosine test had a sensitivity of 76%, a specificity of 95%, a positive predictive value (PPV) of 93%, and a negative predictive value (NPV) of 83%, thus proving to be a suitable noninvasive bedside test for the diagnosis of AVNRT in patients at risk.

Viskin and coworkers developed a test protocol that used ATP to distinguish tachycardias caused by accessory pathways (e.g., AVNRT or AV re-entrant tachycardia [AVRT]) from other forms of tachycardia (e.g., AF).²⁶ They included 146 patients with palpitations of unknown etiology. The ATP test was performed as a bedside test with the patient under continuous ECG monitoring. The investigators started with a bolus of 10 mg ATP followed by additional injections of 10 mg ATP (to a maximum of 60 mg). The test result was considered positive when a dual AV node physiology or a concealed accessory pathway became obvious by a more than 50-ms P-R interval increment or decrement or by the occurrence of AVNRT or AVRT. The test result was considered negative when second- or third-degree heart block occurred without any of the criteria mentioned above. To confirm the test results, EPS was performed on all patients; it showed a sensitivity of 71%, a specificity of 76%, a PPV of 93%, and an NPV of 37% of the ATP test in regard to predicting AVNRT or AVRT.²⁶

Belhassen et al evaluated the diagnostic role of ATP in 96 patients during EPS.²⁷ They showed that ATP injected during sinus rhythm in an incremental dosage, starting at 10 mg to a maximum of 60 mg, identified dual AV nodal physiology in 75% of the patients with inducible AVNRT. In addition, they demonstrated that ATP can be used to confirm the results of a successful radiofrequency ablation of the slow pathway.

Distinguishing Atrial Flutter from Atrioventricular Nodal Re-entrant Tachycardia or Atrioventricular Re-entrant Tachycardia

Atrial flutter with 2 : 1 block normally presents with heart rates of 140 to 150 beats/min. Similarly, AVNRT or AVRT displays a comparable heart rate spectrum. Adenosine can be used to discriminate between AVNRT or AVRT and atrial flutter with 2 : 1 block.⁴ Because of the transient AV block caused by adenosine, electrical atrial activity will be unmasked, showing characteristic P waves and leading to the correct diagnosis of atrial flutter (Figure 70-2).

FIGURE 70-2 Schematic illustration of electrocardiogram changes seen in epinephrine stress test (Shimizu protocol). In long QT (LQT) syndrome types 1 and 2, a paradoxical QTc prolongation can be seen at epinephrine peak concentration. In LQT1, QTc remains prolonged at epinephrine steady-state concentration, and it returns to normal in LQT2. In contrast, in LQT3, no QTc prolongation can be detected either at peak or at steady-state concentration.

Identification of Accessory Bundles by Adenosine and Adenosine 5′-Triphosphate

Furthermore, adenosine, given during sinus rhythm, has been shown to unmask accessory AV conduction bundles with latent pre-excitation, which have only been apparent during atrial arrhythmia or atrial pacing.^28,29 Despite the absence of pre-excitation in sinus rhythm, these patients are at risk of rapid ventricular heart rate when AF occurs. By slowing or transient block of conduction to the ventricles through an AV node, a concealed accessory pathway can be exposed (see Figure 70-2). Garratt et al investigated 22 patients with a history of documented SVT and a normal ECG at sinus rhythm. They demonstrated that adenosine is capable of unmasking latent pre-excitation with high sensitivity and specificity.²⁹

In summary, adenosine is a useful drug for the management and diagnosis of tachycardias. By inducing a transient AV block, re-entry tachycardias involving the AV node are terminated and the ventricular rate is slowed, thus unmasking atrial activity when atrial tachyarrhythmias are present. Adenosine has no influence on VTs.^4,30 Of note, the same effect of transient AV nodal conduction slowing can be achieved by physical methods to stimulate the vagal nerve, including carotid sinus massage, the diving reflex, the Valsalva maneuver, or deep inspiration.³¹

However, adenosine can, as with most drugs, have certain adverse effects. It can induce AF in patients at risk because of its ability to shorten the atrial action potential duration in a dose-dependent and rate-dependent manner.³² Because of its sympathetic stimulation, adenosine also can cause a 1 : 1 conduction in atrial flutter.³³ In addition, in patients with AF and accessory pathways, adenosine can enhance antegrade AV conduction of the high atrial rate via the accessory bundle, resulting in a fast ventricular rate with wide QRS complexes (F_astB_roadI_rregular tachycardia), which also can lead to ventricular fibrillation (VF). Therefore adenosine should always be administered with caution and after taking the required measures to establish the safety of the patient.

Isoproterenol During Electrophysiological Study

Many SVTs are currently treated with radiofrequency ablation procedures. However, inducing the specific arrhythmia during EPS is important before performing an ablation. For this purpose, isoproterenol infusion is widely used in combination with programmed stimulation, especially when programmed atrial stimulation alone fails to induce the clinical arrhythmia.² Furthermore, failure of arrhythmia re-induction after ablation (with or without isoproterenol) confirms the successful outcome of the procedure.

Atrial Fibrillation

Oral et al investigated the role of isoproterenol to assess the inducibility of paroxysmal AF during catheter ablation.³⁴ They enrolled 80 patients with a history of paroxysmal AF and 20 healthy controls receiving an incremental dosage of isoproterenol starting at 5 µg/min followed by 10, 15, and 20 µg/min every 2 minutes or until AF was induced. They induced AF in 84% of patients with AF but in only one of the control subjects (5%). They revealed inducibility of vagotonic AF in 88%, adrenergic AF in 100%, and nonspecific AF in 79%. Overall sensitivity was 88%, and specificity was 95% for induction of AF in patients with paroxysmal AF regardless of the clinical subtype.

In the case of vagally induced AF, carotid sinus massage or ATP at a dosage of 10 to 20 mg can be useful to induce AF.^2,35

Oral et al were able to demonstrate the value of isoproterenol infusion after catheter ablation of paroxysmal AF in predicting clinical outcome more accurately compared with the widely used rapid atrial pacing.³⁶

ATP also can be used for the same purpose.³⁷ Ninomiya et al used 30 mg of ATP after isolation of all four pulmonary veins during isoproterenol infusion in 21 patients with AF. In all patients, electrical isolation was achieved initially. However, spontaneous reconduction was observed in 12 pulmonary veins, with 8 more pulmonary veins showing re-conduction only after ATP administration. Thus their results indicated the usefulness of ATP to detect early reconduction after pulmonary vein isolation.

Arentz et al performed a study on 29 patients with paroxysmal or persistent AF who underwent pulmonary vein isolation.³⁸ They used adenosine at a dose of 12 to 18 mg injected after the successful isolation of pulmonary veins to unmask the so-called dormant conduction, that is, restored conduction through a previously isolated pulmonary vein. Adenosine induced transient conduction in 25% of successfully isolated pulmonary veins. However, a second EPS was performed in 14 patients that revealed a non-significant higher rate of restored conduction in previously “adenosine-positive” pulmonary veins. To identify the potential underlying mechanism, Datino and coworkers studied the effects of adenosine on canine pulmonary veins.³⁹ They illustrated that adenosine selectively hyperpolarized canine pulmonary veins by increasing the inward rectifier potassium current I_KAdo, restoring the excitability of isolated pulmonary veins with dormant conduction.

Further studies are needed to evaluate the safety, reliability, and usefulness of ATP and adenosine in predicting clinical outcome after pulmonary vein isolation in a larger cohort of patients.