Supplemental Extras: Deeper Dive Into Selected Topics

Basic Cardiac Electrophysiology: Mini-Review

This book is devoted to describing the ECG, an invaluable tool in clinical technology that provides essential information about the status of the cardiac rhythm and the effects of certain major abnormalities, including ischemia and infarction, cardiac chamber enlargement, drug toxicity, and life-threatening metabolic disturbances (e.g., severe hyperkalemia). We also emphasize important limitations of the ECG.

Clinicians should be aware that the surface ECG waveforms (as recorded on the usual 12 leads or selected monitor leads) represent the summation of electrical activity generated by enormous numbers of individual cardiac cells (myocytes) in the atria and ventricles. However, the inherent electrical activity of the sinus node, the atrioventricular (AV) node, and the His–Purkinje network (intrinsic pacemakers and specialized conduction system) are not directly recorded. Fortunately, “hidden information” about their normal or abnormal function can often be inferred from the ECG.

As an example, a wide QRS complex may indicate a block in one of the bundle branches. The morphology usually indicates whether the block is in the right or left bundle branch ( Chapter 8 ). Further, as discussed in Chapter 17 , sometimes the key distinction between a nodal versus infranodal location of AV blocks can be made from the surface ECG.

Understanding of the basis of the surface ECG is facilitated by some knowledge about the electrical properties of individual cardiac cells themselves. This subject is one of enormous complexity and ongoing research.

The intent of the following brief section, therefore, is to outline some basic aspects of cardiac electrophysiology. The emphasis is on the action potential , the fundamental electrical cycle of single myocardial cells as they depolarize (activate or discharge) and repolarize (recover or recharge). Readers interested in a more in-depth understanding can refer to the Bibliography.

The Heart as an Electrically Excitable Medium

The heart is an example of a biologically excitable medium . Other examples include the nervous system, the bowel, and the muscular system. Electrically excitable media are capable of propagating waves but also have a refractory period when they cannot be excited.

The electrical excitability of the heart ( Figs. S2.1 and S2.3 ) depends on the facts that normal cardiac cells:

• (1)

  are polarized (charged) under resting conditions, that is, there is a transmembrane potential gradient;

• (2)

  are capable of rapidly discharging (depolarizing) and then more gradually recharging (repolarizing);

• (3)

  can conduct (propagate) electrical currents; and

• (4)

  include specialized cell groups, in particular those constituting the sinus (sinoatrial [SA]) node, that depolarize and repolarize automatically such that one activation–recovery cycle is followed by another and another, and so on. The specialized pacemaker cells possess inherent automaticity that is responsible for reliably maintaining and tuning the rhythmicity of the heart over the full range of physiologic states. Other cardiac cells outside the sinus node (e.g., in the atria and ventricles) have some degree of automaticity. However, their activation usually requires stimulation by neighboring cells and the initiating stimulus for each normal heartbeat starts in the sinus node. The automaticity of the sinus and AV nodes, in turn, are importantly modulated by the autonomic nervous system (sympathetic and parasympathetic branches).

Transmembrane Potential (Voltage) Differences (Gradients)

The polarization of cardiac cells is such that under resting conditions they carry a negative charge on the inside of the cell membrane relative to the outside of the membrane. This transmembrane potential difference is importantly related to the fact that cardiac cell membranes are semipermeable . Under resting conditions, the membrane selectively permits only one species of ion, namely potassium (K ⁺ ), to cross freely, while the membrane is relatively impermeable to other ions, notably sodium (Na ⁺ ) and calcium (Ca ²⁺ ). Consequently, under resting (baseline) conditions the cells accumulate a predominance of K ⁺ ions inside relative to outside, along with a predominance of Na ⁺ and Ca ²⁺ ions outside relative to inside. The exquisitely coordinated, energy-requiring mechanisms for creating these ionic imbalances are complex. They involve a special inward K ⁺ current as well as ion exchangers and ion pumps located within the membrane.

During resting conditions of cardiac cells, the tendency of intracellular K ⁺ ions to move down their concentration gradient toward the outside of the cell is counterbalanced by the “pull” of negatively charged ions (e.g., phosphate) inside the cell that are too big to cross through the membrane. This dynamic “push–pull” process leads to the negative/positive relationship (polarization) of the inside of the cells relative to the outside, creating the nonzero “ equilibrium” potential .

The Action Potential: Key to the Heart’s Electrical Properties

Electrical stimulation perturbs this equilibrium and leads to depolarization and then repolarization associated with the opening and closing of specialized ion channels along the membrane. The channels act like mini-gatekeepers. These currents that result from movements of ions, in turn, produce changes in the transmembrane potential.

When the sequential changes in intracellular voltage of a single heart muscle cell (fiber) are graphed as a function of time, the result is a two-dimensional depiction of the action potential . In contrast, the ECG represents the changes in extracellular potentials of myriads of cells as a function of time. Despite fundamental differences, the intracellular action potential of individual cells (especially ventricular cells) bears important correspondences with the surface QRS-ST-T sequence recorded by the ECG ( Fig. S2.1 ).

All electrically excitable cells have a distinct pattern to their action potential, and the cardiac cell is no exception. We will begin by focusing on the action potential of the ventricles (and Purkinje fibers) as a model. Although we usually think of the activity of ventricles in three sequential stages—resting state, depolarization, and repolarization—the action potential that underlies these stages is actually divided into five phases, denoted as phases 0 through 4, that include these three major states ( Fig. S2.2 ).

By convention, depolarization of the ventricles is termed phase 0. This initial phase is caused by the opening of Na ⁺ channels along the cell membrane. Owing to the electrochemical gradient , there is an initial influx of positively charged Na ⁺ ions into the cell, which has a negative intracellular charge and a relatively lower concentration of Na ⁺ ions. Once a threshold potential (about −50 millivolts [mV] in ventricular cells) is reached, the cells rapidly depolarize as the Na ⁺ channels fully open. Overall, transmembrane voltage (inside vs. outside of the cells) therefore quickly changes from approximately −90 mV to approximately +10 mV.

The cardiac electrical system can be considered as a complex network. Cardiac cells are interconnected by specialized links, called gap junctions . These connections facilitate electrical communication between the myofibers.

Phase 0 of the action potential, representing ventricular depolarization, coincides with the rapid upstroke of the QRS complex of the surface ECG. Not surprisingly, factors that directly impair opening of Na ⁺ channels, including certain drugs and hyperkalemia, tend to widen the QRS complex and slow ventricular conduction.

Phases 1 to 3 represent ventricular repolarization, during which time the ventricular myocytes begin to lose their positive charge.

Phase 1 marks the end of phase 0—specifically, the inactivation of the Na ⁺ channels, causing a cessation of Na ⁺ influx. (There is a slight notch caused by a transient loss of positive voltage because of the outflow of K ⁺ ions.)

Phase 2 of the ventricular action potential is called the plateau phase , during which there is stability of the transmembrane potential. This phase is created by the balance between the inflow and outflow of two positively charged particles, Ca ²⁺ and K ⁺ , respectively.

The plateau phase is unique to the cardiac action potentials of ventricular myocytes (vs. central and peripheral nerves) and is responsible for the relatively prolonged duration of the cardiac myocyte electrical cycle. Of note, during phases 1 and 2 (and the early part of phase 3), the ventricular myocyte is normally incapable of being depolarized again—that is, it is refractory to activation by electrical stimuli.

Of key importance is the entry of Ca ²⁺ ions during the action potential and the release of Ca ²⁺ ions within the working heart muscle cells, causing contraction (shortening) of these cells. This process of electromechanical coupling links the electrical events with the pumping function of the heart.

During phase 3, Ca ²⁺ channels close, shutting off the inflow of the positive Ca ²⁺ current, leaving the efflux of positively charged K ⁺ current unopposed. This drives the transmembrane potential back down toward its resting level of −90 mV.

Phase 4 of the ventricular action potential marks the return to the resting phase.

Fig. S2.3 shows the relationship of all four phases of the ventricular myocyte action potential to the surface ECG complex.

• Phase 0 to 1 corresponds to the QRS complex.

• Phase 2 of the ventricular action potential corresponds to the ST segment. During this phase, the ECG begins to return to baseline because there is no net current flow between cells, which are all at about the same potential.

• Note: Factors that prolong phase 2, such as hypocalcemia and certain drugs, will prolong the ST segment component of the QT interval. Factors such as hypercalcemia or digoxin, which shorten phase 2 of ventricular action potentials, will tend to abbreviate the ST segment phase of the ECG.

• Phase 3, which occurs at somewhat different times in different parts of the ventricular myocardium, corresponds with inscription of the T wave.

• Phase 4 corresponds to the T-Q segment (used as isoelectric baseline of the standard ECG).

Atrial muscle cells have action potentials that resemble ventricular ones but the atrial action potentials are shorter in duration (see Fig. S2.3 ).

Sinus and AV Nodal Action Potentials

Cells in the sinoatrial (SA) node ( Fig. S2.3 ) and AV node have markedly different action potentials from those in atrial and ventricular/Purkinje fibers, which we have been describing up to now. First, the depolarization in these nodal cells is much slower than the rapid phase 0 depolarization in the ventricular cells, and is driven primarily by the “slow current” rather than “rapid” Na ⁺ current. Second, the resting membrane potential is not relatively constant but has a spontaneous drift toward depolarization, such that the cells generate action potentials in an automated way. This spontaneous depolarization is what accounts for the inherent automaticity of the sinus node. The ionic basis of spontaneous depolarization and “pacemaker” currents is a subject of active study. The slow entry of Na ⁺ ions (“funny current”) seems to play an important role.

See http://circ.ahajournals.org/content/115/14/1921.full for a concise review of sinus node function.

Because the spontaneous rate of sinus node cells is relatively faster than that of other pacemaker cells (e.g., in the AV node area) and elsewhere, the sinus node normally dominates the initiation of the heartbeat. Other pacemakers can take over (escape rhythms) if the sinus node fails and sometimes with abnormal conditions that increase the automaticity of cells in other parts of the heart (e.g., the atria, AV junction, or ventricular conduction system). This abnormal automaticity is one mechanism for premature ectopic beats and for some types of tachycardias.

The pacemaker cells do not conduct impulses rapidly, compared with atrial and ventricular cells. Indeed, slow conduction of current across the AV node accounts for most of the PR interval on the ECG, a physiologic delay that allows the ventricles time to fill with blood after atrial contraction and before ventricular contraction.

Finally, it is important to emphasize that the activities of the sinus and AV nodes are importantly influenced by the autonomic nervous system and by certain drugs. For example, increased vagal tone and adenosine both make the resting transmembrane potential of these pacemaker cells more negative, thus decreasing their rate of depolarization and slowing the heart rate and increasing the PR interval. Decreases in vagal (parasympathetic) tone and increases in sympathetic tone have the opposite effect. The autonomic nervous system also effects working cardiac fibers. For examples, the strength (inotropic state) of atrial and ventricular muscle is increased by increased sympathetic (adrenergic) stimulation.

Intracardiac Recordings

The surface ECG, despite its remarkable utility, does not directly record certain essential physiologic events. However, some of these events can be recorded using specialized systems of electrodes positioned within the heart during invasive cardiac electrophysiologic studies (EPS), as shown in Fig. S2.4 .

These intracardiac recordings show that the PR interval normally comprises three sequential subintervals. The first interval (HRA–A, or P-A interval) is due to conduction of the signal from the sinus node in the high right atrium (HRA) through atrial tissue to the AV node. The second one (A–H, usually accounting for the majority of the PR interval on the surface ECG) reflects conduction time through the AV nodal tissue to the bundle of His. The third interval (H–V) represents relatively rapid conduction through the His bundle, the bundle branches, and Purkinje fibers into the ventricles.

These subintervals can be recorded with electrical catheters positioned (1) in the high right atrium (close to the sinus node) and (2) across the tricuspid valve (at the area of AV node, His bundle, and right ventricle).

Visualization of A–H (AV nodal conduction) and H–V (His bundle, or infranodal conduction) intervals is important (see Chapter 17 ) in discrimination of AV delays and second-degree AV blocks into nodal and infranodal types. Infranodal blocks are of particular concern and often require the implantation of a permanent pacemaker. In contrast, prolongation of the PR interval or second-degree AV heart block because of nodal disease is usually not of imminent concern, unless associated with major symptoms (see Chapter 17 ).

Invasive EP studies, as discussed in the text, are also essential in localizing the site(s) of supraventricular and ventricular arrhythmias and in therapeutic interventions using radiofrequency ablation (and other ablation modalities such as cryo- and laser technology). These modalities are used to treat a wide range of tachyarrhythmias, including various types of paroxysmal supraventricular tachycardia (PSVT), atrial flutter, atrial fibrillation, and certain types of ventricular tachycardias.

How Do You Measure the Mean QRS Axis with a Bundle Branch Block?

The mean QRS axis in the frontal plan (QRS axis) is routinely measured from 12-lead ECGs. However, no formal guidelines are given for how to operationally measure the axis when the QRS is widened by a bundle branch block, especially right bundle branch block (RBBB). The prolonged terminal part of the QRS in RBBB reflects delays in right ventricular activation; axis determination is primarily of importance in diagnosing left anterior or left posterior fascicular block. Therefore, a reasonable approach is to estimate the mean frontal plane QRS axis using just the first 80 to 100 msec of the QRS (reflecting activation of the left ventricle). For left bundle branch block and other intraventricular conduction delays (IVCDs), the entire QRS can be used or just the initial 80 to 100 msec. The results will usually be comparable. The challenge of measuring axis with a wide QRS using different parts of the QRS complex is one that could be studied in further detail with contemporary digital recordings and large databases.

What Are the Cutoff Thresholds for Left Anterior Fascicular and Left Posterior Fascicular Blocks?

Confusion and inter-observer variability may arise because different sources and different authors have made different recommendations. The formal threshold for left anterior fascicular block (LAFB) is classically set at −45° not −30°, the latter being the cutoff for left axis deviation. LAFB, by itself, may widen the QRS slightly but usually not beyond 110 to 120 msec. Most cases of pure LAFB are associated with small r waves in the inferior leads and a small q wave in lead aVL (and often lead I). In addition, because the vector loop in LAFB goes in a counterclockwise direction (inferior to superior), the peak of the R wave in aVL will occur just before that in lead aVR. When LAFB and inferior wall myocardial infarction (MI) coexist, leads II, III, and aVF may show frank QS waves, not rS waves, or sometimes they show very small, notched r waves. A QR complex in the inferior leads is not consistent with LAFB because it indicates that the inferior forces are oriented inferiorly and rightward, whereas with LAFB they are oriented leftward and superiorly.

LAFB, because of the posteroinferior orientation of the initial QRS vector, is also often associated with two subtle changes in the precordial QRS complex: (1) Initial r wave progression may be slow with micro q waves (about 10-20 msec in duration) in leads V ₁ and V ₂ . (2) Small s waves are usually seen in the lateral chest leads.

LAFB is one of the most common causes of left axis deviation. In contrast, left posterior fascicular block (LPFB) is one of the least common causes of right axis deviation. Indeed, the latter diagnosis requires excluding left–right arm electrode reversal, normal variants (especially in young adults), rightward mediastinal shift changes in cardiac position, right ventricular overload syndromes (e.g., acute pulmonary embolism, chronic thromboembolic pulmonary hypertension, severe pneumonitis, obstructive or restrictive pulmonary disease), and lateral wall MI (because of loss of lateral QRS forces). In the literature, the frontal plane axis threshold for diagnosing LPFB is variously given between +100° and +120°. Of note, in almost all cases, LPFB accompanies RBBB as part of so-called bifascicular block . The frontal plane leads are often configured in the opposite fashion compared to LAFB—specifically, rS complexes in I and aVL and qR complexes inferiorly. Seeing isolated LPFB is extremely rare; if you are making this diagnosis more than once or twice a year, you have an unusual practice or you are mistaking other, much more common causes of isolated right axis deviation for LPFB.