Techniques of Programmed Stimulation and Entrainment

The terms “programmed stimulation” and “entrainment,” in the context of this article, refer to specific methods of pacing the heart. Typically, these techniques are used to gather information about the cardiac conduction system, which can then be used to guide the treatment of heart rhythm disorders.[1] As an example of its utility, these techniques demonstrated that most ventricular tachycardia in the setting of ischemic heart disease is reentrant rather than automatic.[2] These observations have led to the development of anti-tachycardia pacing as a painless alternative to high-energy implantable cardioverter-defibrillator (ICD) shocks and have been instrumental in guiding the ablative therapy of ventricular and supraventricular arrhythmias.[3]

Programmed stimulation, which is a means of entrainment, is most commonly used during invasive electrophysiologic studies, although it may also be accomplished to some degree through an existing pacemaker or implanted defibrillator. Most of this article focuses on the principles involved, which can be applied in either situation.

This article also discusses some of the historical basis for the techniques and the general electrophysiologic principles involved in programmed stimulation of the heart, although a comprehensive review of the subject is beyond the scope of this article. While these techniques are typically used to guide ablation, the discussion of ablation per se is also beyond the scope of this article. Available guidelines include but are not limited to those from the following medical organizations:

• Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), Asia Pacific Heart Rhythm Society (APHRS), and Latin American Heart Rhythm Society (LAHRS) (2019)[4] : Catheter ablation of ventricular arrhythmias

• EHRA/HRS/APHRS/LAHRS, European Association for Cardio-Thoracic Surgery (EACTS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and International Society for Cardiovascular Infectious Diseases (ISCVID) (2020)[5] : How to prevent, diagnose, and treat cardiac implantable electronic device infections

• EHRA/HRS/APHRS/LAHRS (2020)[6] : Risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population

• HRS, American College of Cardiology (ACC), American Heart Association (AHA)[7] : Guidance for cardiac electrophysiology during the COVID-19 pandemic

• European Society of Cardiology (ESC) (2021)[8] : Prevention of cardiac implantable electronic device infections: guidelines and conventional prophylaxis

The most common indication for programmed stimulation is the evaluation of tachycardias, especially when ablation is planned. Other indications for programmed stimulation include the evaluation of syncope in the setting of structural heart disease, stratification of the risk of sudden death in patients with a history of remote myocardial infarction (MI), assessment of the success of ventricular tachycardia ablation, and evaluation of patients with remote MI who have symptoms suggestive of ventricular arrhythmia.[9] In years past, it was common to perform serial programmed stimulation to assess the efficacy of antiarrhythmic drug therapy; in the current era of routine implantable cardioverter-defibrillator (ICD) use, this is less frequently performed.

When these techniques are used for risk stratification with regard to ventricular arrhythmias, one must recognize that the substrate plays a critical role in determining the value of programmed stimulation. While a large body of evidence supports the use of programmed stimulation in ischemic cardiomyopathy, its use in the evaluation of nonischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and Brugada syndrome is less clear.[10, 11, 12, 13]

While electrocardiography (ECG) and ambulatory monitoring remain the mainstay of diagnosis in suspected bradyarrhythmias, invasive electrophysiologic testing continues to have a role, especially in evaluating sinus and atrioventricular (AV) nodal function when noninvasive means have been unrevealing.

Programmed stimulation has a few absolute contraindications. As a rule, patients with unstable angina should be excluded from any aggressive pacing protocols. Patients with decompensated heart failure should be medically optimized prior to an electrophysiology study or other forms of programmed stimulation except when the heart failure is a result of the arrhythmia being investigated. In some instances, programmed stimulation is performed in the evaluation of hemodynamically unstable rhythms; in these cases, hemodynamic support with intraaortic balloon pumps, catheter-based hemodynamic pumps inserted across the aortic valve, and/or intravenous pressors may be indicated.

When the procedure is performed transvenously, rather than through an existing pacemaker or implantable cardioverter-defibrillator (ICD); bacteremia, deep venous thrombosis at the planned access site, or the presence of an untreated bleeding diathesis are considered absolute contraindications. As with any procedure, the inability to give informed consent is also an absolute contraindication.

The procedural room should be equipped with emergency equipment, including a crash cart and two external defibrillators. The support staff should have appropriate training and experience.

Complication prevention

Careful positioning of diagnostic catheters is always prudent. In particular, the right ventricular catheter should be directed toward the right ventricular septum rather than the true apex, as this is the thinnest part of the ventricle. Patients on chronic steroid therapy are at particular increased risk of cardiac perforation, and extra care should be taken when positioning catheters in this cohort.

Patients should be familiarized with the procedure and the possible complications, including those related to sedation given for the procedure.

Patient instructions

Patients should be made aware of the requirement for bedrest after the procedure is performed when vascular access is required. Written home care instructions should be provided to the patient as well.

The equipment and personnel required for the safe application of these techniques in the electrophysiology laboratory is addressed in detail in a 2014 consensus statement released by the Heart Rhythm Society[14]  as well as a 2020 joint consensus statement by the European Heart Rhythm Association (EHRA), HRS, Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS).[6]

As a rule, because of the potential to induce hemodynamically unstable arrhythmias, resuscitation equipment must be readily available. In addition, when performed invasively, a recording system and electroanatomical mapping system are typically used, as is a fluoroscopic imaging system. As with any procedure that involves sedation, supplemental oxygen, wall suction, and equipment to monitor heart rate, blood pressure, and oximetry are mandatory.

Patients should be kept on nothing by mouth (NPO) status for the procedure.

Anesthesia

As a rule, these procedures are safely performed with conscious sedation. Agents such as midazolam and fentanyl are commonly used for sedation, with adjunctive lidocaine for local anesthesia; 1% lidocaine is preferred, as it has been demonstrated that with higher concentrations and overly liberal infiltration, patients can achieve blood lidocaine levels high enough to alter the electrophysiologic properties of the heart.[15]

In some cases, general anesthesia or deep sedation may be preferred. When the expected procedural time is extensive, the rhythm being investigated is hemodynamically unstable, or the patient is unable to lie still, deeper levels of sedation make for a safer procedure. For small children and younger adolescents, general anesthesia is preferable.

When using deeper levels of sedation, the addition of beta agonists such as isoproterenol may be required to counteract the sympatholysis induced from deep sedation. Mechanical support, such as intra-aortic balloon pumps, may also be required in these cases.

Positioning

In most cases, these procedures are performed in an electrophysiology laboratory under fluoroscopic guidance with the patient in a supine position. Positioning is typically with the arms at the sides to allow for free movement of the imaging camera. When these techniques are performed via an existing pacemaker or implanted defibrillator, the patient is typically supine on a stretcher or bed, although, because no venous sheathes are involved, they may be in a reclining rather than supine position. In all cases, it is imperative that the positioning is such that loss of consciousness will not result in injury.

In the immediate postprocedural period, frequent monitoring of vital signs is mandatory. Typically, vital signs postprocedure are assessed every 15 minutes for the first hour and then every 30 minutes for the subsequent hour. With each assessment of the vital signs, the vascular access sites are checked for signs of bleeding, hematoma, or other vascular complications.

Patients who undergo a diagnostic electrophysiologic study without ablation or insertion of a cardiac rhythm management device afterward are typically discharged to home the same day after 4-6 hours of observation. When an ablation is performed or a device such as a pacemaker or defibrillator is inserted after an electrophysiologic study, the standard of care in most of the United States is overnight observation in a telemetry ward.

Prior to undertaking a study involving programmed stimulation, it is essential to begin with an understanding of what exactly is being investigated and what the clinical scenario is for each individual patient. Relevant information would typically include any electocardiographic (ECG), Holter, mobile cardiac outpatient telemetry (MCOT), or telemetry data that would give an appreciation of the cardiac chamber from which the suspected arrhythmia originates, the tachycardia cycle length, and the most likely mechanism of the arrhythmia (ie, automatic vs reentrant). Other details that can be gleaned from these data include the presence of other "nonclinical" arrhythmias that may be seen during the study but which differ from the one believed to be causing the particular issue being investigated.

As a starting point for the discussion of programmed stimulation, it is helpful to briefly review the concept of reentry. Reentrant rhythms consist of a looping circuit of electrical activation, unlike automatic rhythms, which result from repetitive activation from one or several discrete sites.[16]

For reentry to be possible, certain anatomic and physiologic prerequisites must exist. Specifically, reentry requires the presence of tissues that differ in conduction velocity and refractoriness relative to one another; it also requires an area of functional or anatomical block.

Within this reentrant circuit, a propagating wavefront travels circumferentially around the area of block such that the leading edge (head) of the wavefront is “chasing” its trailing edge (tail). The portion of the circuit between the head and tail of the wavefront is termed the excitable gap. The tissue in the gap is either relatively refractory (partially excitable) or completely repolarized (fully excitable), allowing for continued propagation of the reentrant wavefront.

If the wavefront were to propagate so fast that the head met the tail (ie, arriving at tissue that was just recently depolarized and thus absolutely refractory), the wavefront would be extinguished and the arrhythmia terminated. Therefore, for reentrant circuit to sustain an arrhythmia, the distance from the head to the tail of the wavefront (wavelength) must be shorter than the distance around the circuit (path length). Also essential to sustaining reentry is an area of slow conduction within the circuit. It is the reduced conduction velocity of the propagating wavefront within this area of slowing (akin to speed bumps on a street) that allows for tissue downstream to recover from recent depolarization and once again become excitable.

Practical pearls

Stimulate and record from the same site/catheter. For example, when pacing from the right ventricular catheter during entrainment, the assessment of the post pacing interval should also be measured from the right ventricular catheter.

Use long drive trains, typically about 30 ms less than the tachycardia cycle length, but not faster. This increases the chances of having programmed stimuli fall on repolarized tissue and increases the chances of having a stable morphology.

Ensure that there is capture before proceeding to analyze any response.

Ensure the tachycardia was not terminated and reinitiated during the drive train.

Use the criteria for recognizing entrainment.

Do not assess the post-pacing interval when entrainment has not been confirmed.

A single extra stimulus (N) depolarizes myocardium around its point of origin and then travels toward the reentrant circuit, encountering (1) reentrant circuit tissue that is being actively depolarized and refractory (hence extinguishing the extra stimulus N) or (2) partially or completely excitable tissue (the gap). Within the gap, the extra stimulus N propagates both in the retrograde direction, colliding with the head of the preceding tachycardia wavefront (N - 1), and the anterograde direction, “pushing” against the tail of the propagating tachycardia and driving it around the reentrant circuit, after which it exits the circuit with resumption of the morphology and the rate of the original tachycardia.

A series of stimuli at a preprogrammed rate and sequence can be used to penetrate the reentrant circuit in a manner similar to that outlined above. As the series of stimuli are delivered, if they penetrate the excitable gap, they will propagate in the antegrade and retrograde directions, thereby extinguishing the previous wavefront and generating a new one at a rate determined by the pacing frequency and conductive properties of the tissue.

For example, consider the delivery of a three-beat drive train (N1, N2, N3) delivered at a pacing cycle length (PCL) of 350 ms in an effort to entrain a tachycardia with a fixed cycle length of 380 ms.

The first stimulus (N1) collides with and extinguishes the original tachycardia wavefront N - 1 in the retrograde direction while driving the tachycardia in the anterograde direction, accelerating it to 350 ms from 380 ms.

The following stimulus (N2) propagates in the retrograde direction, collides with and extinguishes the wavefront created by N1, and propagates in an anterograde direction around the circuit until it is extinguished by colliding with the retrograde propagation of stimulus N3 as this penetrates the gap.

Finally, the last stimulus in the drive train N3 completes its journey around the circuit, resulting in the next beat having the same morphology as the original tachycardia. The fact that stimuli N1 and N2 activated some portion of the myocardium in the retrograde or antidromic direction as well as in the antegrade or orthodromic direction leads to those paced complexes having a hybrid or "fused" appearance, looking in part like a purely paced beat and in part like the original tachycardia. The concept of fusion and the particulars of assessing fusion are beyond the scope of this article but are well described elsewhere.[17]

As noted above, during entrainment, the last stimulus of the drive train extinguishes the wavefront of the preceding stimulus in the retrograde direction, and, provided the pacing rate does not exceed the conduction properties of the tissue within the circuit, the stimulus propagates in the anterograde direction going completely around the circuit.

The response of an arrhythmia to entrainment is of critical importance in understanding its mechanism and guiding ablation. In performing this analysis, particular attention is paid to the post-pacing interval and to the sequence of atrial and ventricular events after pacing is discontinued.

The time between the electrogram that resulted in the last entrained beat (N3 in the example above) and the onset of next electrogram measured from the stimulation site is referred to as the post-pacing interval. When the difference between the post-pacing interval and the tachycardia cycle length is 30 ms or less, the pacing site is considered to be within the reentrant circuit. The ability to determine if a particular location is within the circuit is of paramount importance in deciding where to perform ablative therapy. A classic example of this is seen in the treatment of atrial flutter in which the operator confirms that they are “in the circuit” by entrainment before ablating the circuit.

The sequence of events that follows the cessation of entrainment are also key to understanding the nature of an arrhythmia. This sequence of events can be of particular use in distinguishing a focal atrial tachycardia from a reentrant supraventricular tachycardia. In atrial tachycardia, the atrial activation does not depend on ventricular activation; therefore, one expects to see an “A-A-V” response to entrainment. On the contrary, a reentrant supraventricular tachycardia displays an “A-V” response.

While not mandatory, there are several medications that may be employed during the use of programmed stimulation. The choice of agent is dictated by the clinical arrhythmia being investigated. In the case of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) for example, the operator may choose to use a positive chronotropic agent such as isoproterenol to aid in inducing or sustaining the arrhythmia as well as to confirm the success of ablation. Other agents commonly employed in the electrophysiology laboratory during programmed stimulation might include beta blockade, adenosine, non-dihydropyridine calcium channel blockers, or ibutilide, as well as other medications depending on the clinical scenario.

Isoproterenol (Isuprel)

Isoproterenol accelerates AV conduction and decreases the QT interval by increasing the heart rate and reducing temporal dispersion of repolarization.

Metoprolol (Kapspargo Sprinkle, Lopressor, Toprol XL)

Metoprolol is a selective beta-1 adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous administration, carefully monitor blood pressure, heart rate, and ECG.

Adenosine (Adenocard, Adenoscan)

Adenosine transiently blocks conduction through the AV node. It can interrupt reentry pathways through the AV node and restore normal sinus rhythm in paroxysmal SVT, including paroxysmal SVT associated with Wolff-Parkinson-White (WPW) syndrome. Adenosine has a short half-life. It is the preferred medication for IV administration to terminate AVNRT because of its rapid metabolism and generally good safety profile.

Ibutilide (Corvert)

Ibutilide can terminate some atria tachycardias. Ibutilide works by increasing the action potential duration and, thereby, changing atrial cycle-length variability.