Medical School · Year 1 · Cardiovascular · includes a quiz and discussion video

Lecture 2: Cardiac Electrophysiology

Unit 1.7: Cardiovascular System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the ionic basis of the cardiac action potential in different cell types
2. Compare action potentials in pacemaker and non-pacemaker cells
3. Explain the mechanisms of automaticity and pacemaker hierarchy
4. Describe the conduction of electrical impulses through the heart
5. Explain the concepts of refractoriness and its clinical significance
6. Describe the autonomic regulation of cardiac electrophysiology

Resting Membrane Potential

Cardiac cells, like all excitable cells, maintain an electrical potential difference across their plasma membranes at rest. This resting membrane potential is primarily determined by the selective permeability of the membrane to potassium ions.

The intracellular and extracellular ion concentrations create electrochemical gradients that drive ion movement. Potassium concentration is approximately 140 millimolar inside the cell and only 4 millimolar outside, creating a strong outward concentration gradient. Sodium concentration is approximately 10 millimolar intracellularly and 140 millimolar extracellularly, favoring inward movement. Calcium concentration is extremely low inside the cell (0.0001 millimolar) compared to outside (2 millimolar), creating an enormous inward gradient. Chloride is higher outside (100 millimolar) than inside (30 millimolar).

The equilibrium potential for each ion—the membrane potential at which there is no net ion movement—can be calculated using the Nernst equation. For potassium, this is approximately -94 millivolts; for sodium, +60 millivolts; and for calcium, +120 millivolts.

At rest, the membrane is most permeable to potassium through inward rectifier potassium channels, designated IK1. This high potassium permeability drives the resting potential toward the potassium equilibrium potential. The sodium-potassium ATPase continuously expends energy to maintain these concentration gradients, pumping three sodium ions out for every two potassium ions brought in.

Different cardiac cell types maintain different resting potentials. Ventricular myocytes have a stable resting potential of approximately -90 millivolts, close to the potassium equilibrium potential. Atrial myocytes rest at approximately -80 millivolts. In contrast, pacemaker cells of the SA and AV nodes have an unstable resting potential around -60 millivolts, which is crucial for their automaticity.

<image>Panel A: Cardiomyocyte with enlarged plasma membrane showing ion distributions with K+ at 140 mM inside and 4 mM outside, Na+ at 10 mM inside and 140 mM outside, and Ca2+ at 0.0001 mM inside and 2 mM outside. Panel B: Inward rectifier K+ channels (IK1) shown as transmembrane proteins allowing K+ efflux with the Na+/K+-ATPase pump transporting 3 Na+ out and 2 K+ in. Panel C: Voltmeter across the membrane displaying -90 mV resting potential. Panel D: Bar graph comparing resting potentials of ventricular myocyte (-90 mV), atrial myocyte (-80 mV), and SA node cell (-60 mV with dotted line indicating instability).</image>

Ventricular Action Potential

The ventricular action potential is characterized by a prolonged duration of approximately 300 milliseconds—far longer than the 1 to 2 milliseconds typical of nerve action potentials. This extended duration is essential for coordinated cardiac contraction and has distinct phases.

Phase 0 represents rapid depolarization. When the cell is depolarized to threshold (approximately -70 millivolts), voltage-gated sodium channels (Nav1.5, carrying the INa current) open rapidly. The resulting massive sodium influx depolarizes the membrane from -90 millivolts to approximately +30 millivolts within 1 to 2 milliseconds. The upstroke velocity of phase 0 determines conduction velocity through the tissue.

Phase 1 is early repolarization. Sodium channels rapidly inactivate, terminating the sodium current. Simultaneously, transient outward potassium channels (carrying Ito) open briefly, allowing potassium efflux that creates a small notch in the action potential, bringing the potential down to approximately 0 millivolts. The magnitude of this notch varies across the ventricular wall, being more prominent in epicardial cells.

Phase 2, the plateau phase, is unique to cardiac muscle and essential for its function. During this phase lasting 200 to 300 milliseconds, inward calcium current through L-type calcium channels (Cav1.2, carrying ICaL) is balanced against outward potassium currents through the rapid and slow delayed rectifier channels (IKr and IKs). This balance maintains the membrane near 0 millivolts. The plateau phase prevents tetanic contraction and allows complete contraction and relaxation before the next stimulus.

Phase 3 is repolarization. As L-type calcium channels inactivate and potassium efflux through IKr, IKs, and IK1 predominates, the membrane potential returns to its resting value. The shape of the T wave on the electrocardiogram reflects this phase of ventricular repolarization.

Phase 4 represents the stable resting potential maintained by high IK1 conductance. In ventricular myocytes, this phase remains flat until the next action potential is triggered.

<image>Panel A: Ventricular action potential waveform showing Phase 0 (rapid upstroke from -90 to +30 mV with Na+ influx) and Phase 1 (notch to ~0 mV with K+ efflux via Ito). Panel B: Phase 2 plateau at ~0 mV with Ca2+ influx (ICaL) balanced by K+ efflux (IKr, IKs), and Phase 3 repolarization with K+ efflux predominating (IKr, IKs, IK1). Panel C: Ion current traces (INa, Ito, ICaL, IKr, IKs, IK1) aligned temporally with the action potential showing magnitude and direction. Panel D: Three states of the sodium channel with diagrams showing closed (resting), open (phase 0), and inactivated (phases 1-2) configurations.</image>

Pacemaker Action Potential

Pacemaker cells in the SA and AV nodes have fundamentally different action potentials that enable spontaneous, rhythmic depolarization without external stimulation.

Unlike ventricular cells, pacemaker cells lack a stable resting potential. Their maximum diastolic potential is approximately -60 millivolts, less negative than ventricular cells because they express fewer IK1 channels. This less negative potential means fast sodium channels are chronically inactivated and unavailable, so depolarization in pacemaker cells relies on different mechanisms.

Phase 4 in pacemaker cells shows spontaneous depolarization, called the pacemaker potential or diastolic depolarization. Three mechanisms contribute to this crucial phase. First, the funny current (If), a mixed sodium-potassium current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, activates when the membrane hyperpolarizes below approximately -50 millivolts. Despite its name, this inward current is "funny" because it activates with hyperpolarization rather than depolarization. Second, T-type calcium channels (ICaT) contribute to late diastolic depolarization. Third, the calcium clock mechanism involves spontaneous calcium release from the sarcoplasmic reticulum through ryanodine receptors, which activates the sodium-calcium exchanger (NCX), generating an inward current (3 Na+ in for 1 Ca2+ out).

Phase 0 in pacemaker cells is slow and driven by L-type calcium channels rather than fast sodium channels. The upstroke velocity is much slower than in ventricular cells, which explains the slow conduction through the AV node.

Phase 3 involves repolarization through potassium efflux via delayed rectifier potassium channels. There is no plateau phase.

<image>Panel A: Pacemaker action potential with unstable phase 4 showing gradual spontaneous depolarization from -60 mV to threshold (-40 mV) with contributing currents If, ICaT, and NCX labeled. Panel B: Slow phase 0 driven by ICaL reaching +10 mV and rapid phase 3 repolarization via IK with no plateau phase present. Panel C: Ventricular action potential comparison with stable phase 4 at -90 mV, rapid phase 0, notch, prominent plateau, and gradual phase 3. Panel D: Key differences table (resting potential, phase 0 mechanism, plateau presence, phase 4 slope) with inset showing HCN channel structure and activation by hyperpolarization.</image>

Automaticity and Pacemaker Hierarchy

All parts of the cardiac conduction system possess the ability to spontaneously generate action potentials, a property called automaticity. However, these regions depolarize at different intrinsic rates, creating a hierarchy that normally keeps the heart beating in an orderly fashion.

The SA node has the fastest intrinsic rate at 60 to 100 beats per minute, making it the dominant pacemaker under normal conditions. The AV node depolarizes at 40 to 60 beats per minute. The bundle of His has an intrinsic rate of 30 to 40 beats per minute, and Purkinje fibers are slowest at 20 to 30 beats per minute.

Overdrive suppression is the mechanism by which faster pacemakers suppress slower ones. When the SA node fires, it depolarizes the AV node and other potential pacemakers before they reach threshold, resetting their diastolic depolarization. As long as the SA node functions normally, slower pacemakers never have the opportunity to fire. If the SA node fails, the AV node can assume pacemaking function, producing an escape rhythm at 40 to 60 beats per minute. If the AV node also fails, ventricular escape rhythms from the Purkinje system occur at very slow rates.

Several factors modulate automaticity. Sympathetic stimulation increases the slope of phase 4 depolarization by enhancing If and ICaL, thereby increasing heart rate. Parasympathetic stimulation decreases the slope of phase 4 by reducing If and activating acetylcholine-gated potassium channels (IKACh), which hyperpolarizes the maximum diastolic potential. Hyperthyroidism increases beta-receptor sensitivity and heart rate. Hypothermia slows channel kinetics and reduces automaticity.

<image>Panel A: Heart with conduction system showing intrinsic rates labeled: SA node (60-100 bpm), AV node (40-60 bpm), bundle of His (30-40 bpm), and Purkinje fibers (20-30 bpm) with action potential waveforms from each region. Panel B: Overdrive suppression demonstration with SA node action potentials spreading to the AV node and resetting its phase 4 before reaching threshold. Panel C: Escape rhythm formation when SA node fails showing AV node action potentials taking over at 50 bpm. Panel D: Autonomic modulation showing sympathetic stimulation (steeper phase 4 slope, faster rate) and parasympathetic stimulation (shallower phase 4, hyperpolarized MDP, slower rate).</image>

Conduction Through the Heart

The spread of electrical impulses through the heart follows a precise sequence that ensures coordinated contraction of atria before ventricles.

Conduction velocity varies dramatically across cardiac tissues, determined by factors including cell size, gap junction density, and action potential characteristics. Atrial muscle conducts at approximately 0.5 meters per second. The AV node conducts extremely slowly at 0.05 meters per second—one-tenth the speed of atrial muscle. This slow conduction is due to small cell size, few gap junctions, and the slow calcium-dependent upstroke. The bundle of His conducts at 1 meter per second, and Purkinje fibers are the fastest conductors at 2 to 4 meters per second, owing to their large cell diameter and abundant gap junctions. Ventricular muscle conducts at approximately 0.5 meters per second.

The normal sequence of activation begins when the SA node fires. The impulse spreads through the atrial myocardium, reaching the AV node. Internodal pathways—anterior, middle, and posterior—may facilitate preferential conduction to the AV node, though this remains debated. Atrial depolarization produces the P wave on the ECG.

The AV node imposes a critical delay of approximately 100 milliseconds, represented by the PR interval on the ECG. This delay allows atrial contraction to complete and the atria to empty into the ventricles before ventricular systole—the so-called atrial kick. The AV node is the only normal electrical connection between atria and ventricles, as the fibrous cardiac skeleton otherwise electrically insulates them.

From the AV node, the impulse travels through the bundle of His, which penetrates the fibrous skeleton, then divides into right and left bundle branches in the interventricular septum. Purkinje fibers distribute the impulse rapidly throughout the ventricular subendocardium, ensuring near-simultaneous activation. Ventricular depolarization proceeds from endocardium to epicardium and from apex toward base, producing the QRS complex.

<image>Panel A: SA node firing at 0 ms shown as yellow burst with atrial depolarization spreading as blue wave through both atria at 40-60 ms with P wave on ECG. Panel B: Slow AV node conduction at 60-160 ms depicted as bottleneck with closely packed small cells corresponding to PR segment on ECG. Panel C: Rapid conduction through bundle of His at 160-180 ms into right and left bundle branches traveling down the septum. Panel D: Purkinje network activation at 180-200 ms with endocardium-to-epicardium and apex-to-base arrows, QRS on ECG, and conduction velocity table (atrial 0.5, AV node 0.05, His 1, Purkinje 2-4, ventricular 0.5 m/s).</image>

Refractoriness

The refractory period is the interval during which a cardiac cell cannot be re-excited or is difficult to re-excite. This property is essential for preventing tetanic contraction and maintaining the orderly sequence of depolarization.

The absolute refractory period, also called the effective refractory period (ERP), encompasses phases 0, 1, 2, and early phase 3 of the action potential. During this time, no stimulus of any strength can elicit another action potential because sodium channels are either open or inactivated. The molecular basis lies in the three conformational states of the sodium channel: closed (resting, can be opened), open (conducting), and inactivated (cannot open regardless of stimulus). During the plateau, sodium channels remain inactivated because the membrane has not repolarized sufficiently for channels to recover.

The relative refractory period occurs during late phase 3 as the membrane repolarizes. During this period, a stronger-than-normal stimulus can trigger an action potential, but it will have a reduced upstroke velocity and may conduct slowly or not at all. This is because some but not all sodium channels have recovered from inactivation.

The supernormal period is a brief interval at the end of phase 3 when the membrane is slightly more excitable than normal. Though rarely of clinical significance, it represents a point when even weaker stimuli can trigger depolarization.

The long refractory period of cardiac muscle, essentially the entire action potential duration, prevents re-excitation during contraction. This contrasts with skeletal muscle, where the refractory period is much shorter than the contraction, allowing tetanic contractions. The cardiac muscle design ensures that each contraction is followed by relaxation, allowing the ventricles to fill before the next contraction.

Heterogeneity in action potential duration across the ventricular wall creates differences in refractory periods. M cells in the midmyocardium have the longest action potential duration and refractory period. Epicardial cells have shorter action potentials than endocardial cells. This heterogeneity contributes to the normal pattern of repolarization and can become arrhythmogenic when exaggerated.

<image>Panel A: Ventricular action potential with absolute refractory period (ERP) as red-shaded region covering phases 0, 1, 2, and early phase 3 labeled "No response to any stimulus." Panel B: Relative refractory period (RRP) as yellow-shaded region in late phase 3 and supernormal period as small green zone at transition to phase 4. Panel C: Sodium channel state transitions showing closed to open (phase 0) to inactivated (phases 1-2) to closed (phase 4) with stimulus response inset for each period. Panel D: Ventricular wall cross-section showing action potential duration differences in epicardium (shortest), midmyocardium/M cells (longest), and endocardium (intermediate).</image>

Excitation-Contraction Coupling

The link between electrical excitation and mechanical contraction in cardiac muscle is called excitation-contraction coupling. The central mechanism is calcium-induced calcium release (CICR), which amplifies the calcium signal needed for contraction.

During the plateau phase of the action potential, L-type calcium channels open and allow calcium to enter the cell. Unlike skeletal muscle, where sarcoplasmic reticulum calcium release is triggered by voltage alone, cardiac muscle requires this initial calcium influx. The entering calcium binds to ryanodine receptors (RyR2) on the sarcoplasmic reticulum membrane, triggering them to open and release a much larger amount of calcium stored within the SR. This amplification is the "calcium spark" that underlies contraction.

The rise in cytoplasmic calcium from approximately 0.1 micromolar to 1 micromolar allows calcium to bind to troponin C on the thin filaments. This binding induces a conformational change that moves tropomyosin away from actin's myosin-binding sites, permitting cross-bridge cycling and force generation.

Relaxation requires removal of calcium from the cytoplasm. Approximately 75 percent of the calcium is returned to the sarcoplasmic reticulum by the sarco-endoplasmic reticulum calcium-ATPase (SERCA), which is regulated by phospholamban. The remaining calcium is extruded from the cell primarily by the sodium-calcium exchanger (NCX), which exchanges three sodium ions in for one calcium ion out, generating a small inward current. A small amount is also removed by the plasma membrane calcium ATPase.

A critical difference from skeletal muscle is the absolute requirement for extracellular calcium. Removing extracellular calcium abolishes cardiac contraction because there is no trigger for SR calcium release. The L-type calcium current serves as both the trigger for CICR and contributes directly to the cytoplasmic calcium rise.

<image>Panel A: T-tubule membrane with action potential reaching L-type calcium channels (Cav1.2) allowing calcium entry, which binds to ryanodine receptors (RyR2) on the sarcoplasmic reticulum membrane. Panel B: RyR2 opening releases calcium flood from SR ("Calcium spark") raising cytoplasmic calcium from 0.1 to 1 micromolar. Panel C: Calcium binding to troponin C causes tropomyosin movement exposing myosin binding sites on actin allowing cross-bridge formation. Panel D: Relaxation via SERCA pumps returning calcium to SR (regulated by phospholamban) and NCX exchanging 3 Na+ in for 1 Ca2+ out, with bar graph showing calcium removal contributions (SERCA 75%, NCX 23%, other 2%).</image>

Autonomic Regulation

The autonomic nervous system profoundly influences cardiac electrophysiology through sympathetic and parasympathetic pathways.

Sympathetic stimulation produces four main effects on the heart, each designated with the prefix "positive." Positive chronotropy refers to increased heart rate, achieved by increasing the slope of phase 4 depolarization in pacemaker cells through enhanced If and ICaL. Positive dromotropy means faster conduction, particularly through the AV node, mediated by increased calcium current. Positive inotropy indicates increased contractility, resulting from enhanced calcium influx through L-type channels and increased SR calcium release and uptake. Positive lusitropy refers to faster relaxation, achieved by phosphorylation of phospholamban, which disinhibits SERCA and accelerates calcium reuptake.

The molecular pathway underlying sympathetic effects involves beta-1 adrenergic receptors on cardiomyocytes. Norepinephrine binds to these receptors, activating the stimulatory G protein (Gs), which activates adenylyl cyclase to produce cyclic AMP. Elevated cAMP activates protein kinase A (PKA), which phosphorylates multiple targets: L-type calcium channels (increasing calcium influx), ryanodine receptors (enhancing calcium release), phospholamban (accelerating relaxation), and troponin I (increasing cross-bridge cycling rate).

Parasympathetic stimulation, mediated by the vagus nerve, produces opposite effects. Negative chronotropy results from decreased If current and activation of acetylcholine-gated potassium channels (IKACh), which hyperpolarize pacemaker cells and reduce the slope of phase 4. Negative dromotropy involves slowed AV conduction through similar mechanisms. Parasympathetic effects on ventricular contractility are minimal because vagal innervation of the ventricles is sparse.

The molecular pathway involves M2 muscarinic receptors coupled to inhibitory G proteins (Gi). Acetylcholine binding reduces cAMP levels, opposing sympathetic effects. Additionally, the beta-gamma subunit of Gi directly activates IKACh, providing a rapid mechanism for heart rate reduction.

At rest, parasympathetic tone predominates, which is why the resting heart rate of approximately 70 beats per minute is substantially lower than the SA node's intrinsic rate of approximately 100 beats per minute. Vagotomy (cutting the vagus nerve) produces tachycardia, unmasking the intrinsic rate.

<image>Panel A: Sympathetic pathway in green showing norepinephrine binding to beta-1 receptors activating Gs, adenylyl cyclase, cAMP, and PKA with target phosphorylation sites on L-type Ca2+ channel, RyR2, phospholamban, and troponin I. Panel B: Sympathetic effects listed (increased chronotropy, dromotropy, inotropy, lusitropy) with pacemaker action potential showing steeper phase 4 slope. Panel C: Parasympathetic pathway in blue showing acetylcholine binding to M2 receptors activating Gi to decrease cAMP and beta-gamma subunits opening IKACh channels with effects (decreased chronotropy, dromotropy). Panel D: Comparison of resting heart rate (70 bpm with parasympathetic dominance), intrinsic SA node rate (100 bpm), and sympathetically stimulated rate (110+ bpm) with pacemaker action potential showing hyperpolarized MDP and shallower phase 4.</image>

Electrocardiogram Correlation

The surface electrocardiogram represents the summation of all cardiac electrical activity, and understanding its relationship to cellular events is fundamental.

The P wave corresponds to atrial depolarization, reflecting the spread of action potentials through atrial myocardium. The PR interval includes both the P wave and the isoelectric PR segment, representing the time from the beginning of atrial depolarization to the beginning of ventricular depolarization. The PR segment reflects the slow conduction through the AV node, which produces too little electrical activity to be detected on the surface ECG.

The QRS complex represents ventricular depolarization. This corresponds to phase 0 of the ventricular action potential, when fast sodium channels open and cause rapid depolarization. The narrow width of the normal QRS (less than 120 milliseconds) reflects the rapid, coordinated activation of the ventricles via the specialized conduction system.

The ST segment corresponds to the plateau phase (phase 2) of the ventricular action potential. During this phase, all ventricular cells are at similar potentials, creating an isoelectric baseline. ST elevation or depression occurs when there are voltage gradients during this phase, as occurs with myocardial injury or ischemia.

The T wave represents ventricular repolarization, corresponding to phase 3 of the action potential. The T wave is normally upright in most leads despite repolarization being the opposite electrical process to depolarization. This occurs because repolarization proceeds from epicardium to endocardium—opposite to the direction of depolarization—creating a double-negative that results in a positive deflection.

The QT interval encompasses all ventricular electrical activity, from the beginning of depolarization to the completion of repolarization. It reflects the action potential duration and varies inversely with heart rate, shortening at faster rates.

<image>Panel A: Complete PQRST complex on ECG paper with time scale and voltage calibration aligned temporally with ventricular action potential below. Panel B: P wave labeled "Atrial depolarization" with PR interval spanning to QRS start and PR segment corresponding to AV nodal conduction through small cells. Panel C: QRS complex aligned with phase 0 (ventricular depolarization via INa), ST segment aligned with phase 2 plateau (all cells at similar potential). Panel D: T wave aligned with phase 3 (ventricular repolarization) with arrows showing epicardium-to-endocardium direction, QT interval spanning entire AP, and inset explaining upright T wave physiology.</image>

Clinical Applications

Understanding cardiac electrophysiology illuminates the mechanisms of ion channelopathies, arrhythmias, and their treatments.

Long QT syndrome encompasses inherited disorders caused by mutations affecting ion channels that prolong the ventricular action potential. Type 1 (LQT1) results from loss-of-function mutations in KCNQ1, which encodes the slow delayed rectifier potassium channel (IKs), reducing repolarizing current. Type 2 (LQT2) involves mutations in KCNH2 (HERG), affecting the rapid delayed rectifier (IKr). Type 3 (LQT3) results from gain-of-function mutations in SCN5A, the cardiac sodium channel gene, causing persistent inward sodium current during the plateau. The prolonged QT interval predisposes to a dangerous polymorphic ventricular tachycardia called torsades de pointes. Triggers vary by subtype: swimming and exertion for LQT1, auditory stimuli for LQT2, and rest or sleep for LQT3.

Brugada syndrome results from loss-of-function mutations in SCN5A, reducing sodium current. This creates a distinctive ECG pattern with coved ST elevation in leads V1 to V3 and carries risk of ventricular fibrillation and sudden death, particularly during rest and sleep when vagal tone is high.

Antiarrhythmic drugs are classified based on their primary electrophysiologic mechanism. Class I drugs block sodium channels with varying kinetics: class Ia drugs (quinidine, procainamide) have intermediate kinetics and also block potassium channels, prolonging the action potential; class Ib drugs (lidocaine, mexiletine) have fast kinetics and preferentially bind inactivated channels; class Ic drugs (flecainide, propafenone) have slow kinetics and markedly slow conduction. Class II drugs are beta-blockers that reduce sympathetic stimulation. Class III drugs (amiodarone, sotalol) block potassium channels, prolonging repolarization. Class IV drugs (verapamil, diltiazem) block L-type calcium channels, slowing conduction through the AV node.

Electrolyte disturbances profoundly affect cardiac electrophysiology. Hyperkalemia depolarizes the resting membrane potential, inactivating sodium channels, slowing conduction, and widening the QRS. Severe hyperkalemia can cause sine wave patterns and cardiac arrest. Hypokalemia prolongs the action potential by reducing potassium currents, manifesting as U waves and QT prolongation. Hypocalcemia prolongs the plateau phase and QT interval, while hypercalcemia shortens it.

<image>Panel A: Long QT Syndrome showing ECG strips with prolonged QT in LQT1, LQT2, and LQT3 with action potentials demonstrating delayed repolarization from reduced IKs, IKr, and persistent INa (genes KCNQ1, KCNH2, SCN5A) with torsades de pointes initiation. Panel B: Brugada syndrome showing Type 1 ECG pattern with coved ST elevation in V1-V3 and diagram of epicardial action potential dome loss from reduced INa creating transmural voltage gradient. Panel C: Hyperkalemia progression with ECG at K+ 5.5 (peaked T), 7.0 (wide QRS, flat P), and 8.5 mEq/L (sine wave) with action potentials showing progressive resting potential depolarization. Panel D: Table of antiarrhythmic drug classes with mechanisms, ECG effects, and clinical uses.</image>

Summary

The ventricular action potential has five phases: phase 0 involves fast sodium influx through Nav1.5 channels causing rapid depolarization; phase 1 is early repolarization via transient outward potassium current; phase 2 is the plateau phase where L-type calcium current balances delayed rectifier potassium currents; phase 3 is repolarization as potassium efflux predominates; and phase 4 is the stable resting potential maintained by inward rectifier potassium channels.

Pacemaker cells have an unstable phase 4 due to the funny current (If) and calcium clock mechanism, enabling spontaneous depolarization. The pacemaker hierarchy ensures orderly activation: SA node at 60 to 100 beats per minute dominates over AV node at 40 to 60 beats per minute and Purkinje fibers at 20 to 30 beats per minute.

The AV node provides a critical 100-millisecond delay for atrial contraction to complete before ventricular activation. The long refractory period of cardiac muscle prevents tetanic contraction, allowing complete contraction and relaxation cycles.

Excitation-contraction coupling occurs through calcium-induced calcium release, where L-type calcium channel opening triggers ryanodine receptor release of sarcoplasmic reticulum calcium stores.

Sympathetic stimulation increases heart rate, conduction, contractility, and relaxation through cAMP-dependent phosphorylation of multiple targets. Parasympathetic stimulation decreases heart rate and AV conduction via M2 receptors that reduce cAMP and activate IKACh channels.

Key Terms

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