Cardiovascular Physiology: Electrical Activity of the Heart

Cardiac Electrophysiology and Conduction System

  • Key Objectives:
    • Understand the electrophysiology of the heart and conduction system.
    • Understand how the conduction system structure and function underpin CV pathophysiology and therapeutics.
    • Cover key elements for exam success.
    • Cover key principles:
      • Form relates to Function.
      • Regulation of cardiac conduction at the physiological level.
      • How electrical measurements (ECG) relate to normal physiology and pathophysiology.

Topics Covered

  • Cardiac action potential
  • Excitation-contraction coupling
  • Calcium signaling in myocytes
  • Initiation of the action potential in the sino-atrial node
  • Autonomic control of heart rate
  • Propagation of the action potential: syncytium and specialized conduction system
  • Electrocardiogram (ECG): Einthoven’s triangle, standard, augmented, and precordial leads
  • Cardiac axis and deviation
  • Arrhythmias, fibrillation, and heart block

Syncytium

  • Cells interconnected by specialized membranes with gap junctions.
  • Found in heart muscle cells and certain smooth muscle cells.
  • Synchronized electrically during an action potential.

Conduction Pathway

  • Origin: Sinoatrial (SA) node in the right atrium.
    • Primary pacemaker of the heart.
  • Impulse spread:
    • Atrial myocardium (lacks specialized conduction tissue).
    • Atrioventricular (AV) node.
    • Bundle of His.
    • Left and right bundle branches.
    • Purkinje fibers (stimulate ventricular myocardium).

Conduction Velocities

  • Atrial and ventricular muscle: slow conduction.
  • AV node: very slow conduction.
    • Provides physiological delay for ventricular filling.
  • Specialized conduction tissue (e.g., Purkinje fibers): very rapid conduction.
    • Ensures rapid and coordinated ventricular contraction.

Functional Importance of Conduction Speed Variation

  • Sequential activation of atria and ventricles.
  • Optimal ventricular filling and ejection.

Comparison to Nerve Action Potentials

  • Cardiac action potential starts with a rapid upstroke (similar to nerve and skeletal muscle).
  • Differs by including a plateau phase due to delayed repolarization.

Plateau Phase

  • Critical for:
    • Full ventricular contraction.
    • Ensuring prolonged myocardial contraction for effective cardiac output.
    • Efficient blood ejection from the ventricles.
  • Without the plateau phase, ventricles would not have enough time to empty fully during systole, reducing ejection fraction and compromising cardiac function.

Ion Concentrations and Nernst Potentials

  • Potassium (K⁺):
    • [K^+]_{out} = 5mM
    • [K^+]_{in} = 110mM
    • E_K = -90mV
  • Sodium (Na⁺):
    • [Na^+]_{out} = 145mM
    • [Na^+]_{in} = 10mM
    • E_{Na} = +60mV

Role of Potassium (K⁺)

  • Intracellular concentration is high; extracellular concentration is low.
  • Outward current: Potassium ions move out of the cell, contributing to the resting membrane potential.
  • Equilibrium potential: ~-90 mV (close to the resting potential of cardiac myocytes).
  • Key role: Potassium channels remain open, maintaining a steady outward current, determining the membrane potential.

Role of Sodium (Na⁺)

  • Extracellular concentration is high; intracellular concentration is low.
  • Inward current: Sodium moves inward when channels open, leading to depolarization.
  • Equilibrium potential: ~+60 mV, close to the threshold for action potential initiation.
  • At rest: Sodium channels are closed, making the membrane highly impermeable to sodium.
  • During depolarization: Opening of sodium channels allows influx, shifting membrane potential from ~-80 mV to +40 mV.

Goldman-Hodgkin-Katz Equation

  • Calculates the membrane potential by considering the relative permeability of ions (K⁺, Na⁺, Ca²⁺, Cl⁻) and their concentration gradients across the membrane.

Initial Rapid Depolarization

  • Results from positive feedback at the Na⁺ channels.
  • Small initial depolarization increases gradually.
  • Approaches a threshold (-60 to -70 mV).
  • Once threshold is reached, a rapid upstroke occurs as many voltage-gated sodium channels open, allowing an influx of sodium ions into the cell.

Sodium Channel States

  • Three states: open, closed (poised), and inactive.
  • Switches to the inactive state shortly after opening.
  • Can only return to the closed state after repolarization.
  • The inability of Na⁺ channels to open from the inactive state leads to a refractory period.

Refractory Period

  • Time between depolarization and full repolarization.
  • Cell cannot initiate another action potential (or is less likely to).
  • Reflects the transition from the inactive to the closed state.
  • Essential for maintaining proper cardiac rhythm, preventing arrhythmias, and ensuring the unidirectional nature of AP.

Resting Membrane Potential

  • Inside of the cell is negative at rest, primarily due to the outward movement of potassium (K⁺).
  • Establishes a resting membrane potential of approximately –80 mV.
  • During an action potential, voltage-gated sodium (Na⁺) channels open, allowing Na⁺ to flow inward, making the membrane potential more positive (shifts from around –80 mV to +40 mV).

Spread of Depolarization

  • The depolarizing current spreads passively to adjacent regions of the membrane.
  • This current can leak in both forward and backward directions along the fiber.

Prevention of Backward Conduction

  • Refractory period: In recently depolarized areas, Na⁺ channels are inactivated and cannot reopen immediately.
  • Only the forward region, where Na⁺ channels are still closed and excitable, can be depolarized.

Absolute Refractory Period (ARP)

  • Occurs immediately after depolarization.
  • All Na⁺ channels are inactive.
  • No new action potential can be generated, no matter how strong the stimulus.
  • Ensures heart muscle has time to contract and begin relaxing without premature re-excitation.

Relative Refractory Period (RRP)

  • Follows the absolute phase, during late repolarization.
  • Some Na⁺ channels have recovered and returned to the closed (resting) state.
  • A very strong action potential could trigger another action potential if it surpasses the threshold.
  • The action potential would be abnormal or weaker since not all channels are ready.

Phases of the Cardiac Action Potential

  • Phase 0 – Rapid Depolarization
    • Triggered when the membrane potential shifts from –80 mV to +40 mV.
    • Caused by a sudden, transient increase in sodium permeability (PNa).
    • Voltage-gated Na⁺ channels open, leading to a rapid influx of Na⁺.
    • Generates the sharp upstroke of the action potential.
  • Phase 1 – Early Repolarization
    • Na⁺ channels quickly inactivate, and PNa falls sharply.
    • A brief K⁺ efflux occurs, causing a small downward deflection.
  • Phase 2 – Plateau Phase
    • Maintained depolarization around 0 mV.
    • Caused by:
      • Opening of voltage-gated Ca²⁺ channels → Ca²⁺ influx, moves potential towards the threshold.
      • Reduced K⁺ efflux due to temporary closure of K⁺ channels.
    • Prolonged depolarization, is critical for sustained contraction and ventricular emptying.
    • Unique to cardiac muscle, allows time for efficient blood ejection before repolarization.
  • Phase 3 – Repolarization
    • Occurs when:
      • Ca²⁺ channels close → stops positive influx.
      • K⁺ channels reopen → restores outward K⁺ current.
    • Outward movement of K⁺ drives the membrane back toward resting potential (~–80 mV).
    • The cell repolarizes when PK and PCa return to their original values.
  • Phase 4 – Resting Potential
    • Maintained mainly by:
      • Open K⁺ channels → constant K⁺ efflux.
      • Low permeability to Na⁺ and Ca²⁺.
    • PK is high, keeping the cell interior electrically negative.
    • No hyperpolarization.

Excitation-Contraction Coupling

  • T-tubules: Invaginations of the cardiac cell membrane that transmit depolarization deep into the muscle.
  • L-type Calcium Channels: Located in the dyadic cleft, open during depolarization, allowing calcium influx into the cell.
  • Calcium-Induced Calcium Release (CICR): Influx of calcium through L-type channels binds to ryanodine receptors on the sarcoplasmic reticulum (SR), triggering further calcium release from the SR.
  • Troponin and Tropomyosin Conformational Changes: Released calcium binds to troponin, inducing a conformational change, shifting tropomyosin away from the myosin-binding sites on actin, exposing them for myosin binding.
  • Cross-Bridge Formation: Exposed actin binding sites allow myosin heads to bind to actin, forming cross-bridges and initiating contraction.
  • Relaxation: Calcium removal from troponin restores the tropomyosin blocking action, leading to muscle relaxation. Calcium is pumped back into the sarcoplasmic reticulum for storage.

Calcium Removal

  • Crucial for muscle relaxation after contraction.
  • SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase) moves calcium from the cytosol back into the sarcoplasmic reticulum (SR), which stores calcium for future contractions.
  • PMCA (plasma membrane calcium ATPase) moves calcium from the cytosol to the extracellular space.
  • Both pumps are ATP-dependent, meaning cardiac muscle has high energy demands to remove calcium during relaxation.
  • These pumps help restore calcium balance after contraction and are critical for the heart to prepare for the next cycle.

Regulation of SERCA Activity

  • SERCA is negatively regulated by Phospholamban (PLN).
  • SERCA activity is regulated by phospholamban, which is phosphorylated by protein kinase A (PKA).

Inotropy and Chronotropy

  • Inotropy: The heart's contractile strength.
    • Positive inotropy increases contraction (e.g., sympathetic stimulation).
    • Negative inotropy decreases contraction (e.g., parasympathetic influence, heart failure).
  • Chronotropy: The heart rate.
    • Positive chronotropy increases heart rate (e.g., sympathetic activation via β₁-adrenergic receptors).
    • Negative chronotropy decreases heart rate (e.g., parasympathetic activation via the vagus nerve).

PKA Modulation

  • PKA modulates both the Ca²⁺ channels and phospholamban.
  • Increases the Ca²⁺ current but inhibits phospholamban (PLN).
  • Phospholamban negatively regulates SERCA, so the net effect is that PKA stimulates SERCA.
  • PKA phosphorylation of phospholamban relieves this inhibition, allowing SERCA to pump calcium more effectively.
  • During sympathetic activation, noradrenaline increases cAMP, activating PKA, which phosphorylates L-type calcium channels, triggering a greater calcium influx into the cell and enhancing calcium release from the SR, thus strengthening contractions and influencing heart rate.
  • Relaxation is crucial because it allows the heart to fully empty and then refill with blood before the next contraction, ensuring efficient cardiac output.

Sodium-Potassium ATPase

  • Sodium-potassium ATPase (ATP-dependent) regulates calcium removal by setting the gradient for the sodium-calcium exchanger.
  • Cardiac glycosides (e.g., digoxin) inhibit sodium-potassium ATPase, causing sodium accumulation and reducing calcium removal via the sodium-calcium exchanger, leading to increased intracellular calcium and enhanced contraction force.

Ischemia

  • Restricted blood flow depletes ATP as the mitochondria requires oxygen for ATP production, impairing calcium removal as the pumps require ATP and causing calcium overload.
  • Excess calcium in the mitochondria disrupts ATP production, opening the mitochondrial permeability transition pore (mPTP), causing mitochondrial swelling and rupture, and releasing cytochrome c, triggering apoptosis.
  • Without ATP, the cell cannot maintain ion balance, leading to necrosis (uncontrolled cell death).

Cardiac Action Potential Duration

  • The cardiac action potential lasts ~300 ms and aligns with changes in calcium permeability.
  • Calcium influx follows depolarization, triggering intracellular calcium rise, which initiates contraction—calcium is essential for force generation.

SA Node Activity

  • The sinoatrial (SA) node, the heart’s pacemaker, initiates action potentials and rhythmic contractions.
  • Modulated by the autonomic nervous system; sympathetic stimulation (adrenaline or noradrenaline) increases heart rate, and parasympathetic activation (acetylcholine) slows it down.
  • Elevations in the concentration of adrenaline in the plasma will activate the SA node to increase the heart rate.

SA Node as Pacemaker

  • Fires spontaneous action potentials due to a lack of stable resting potential.
  • Gradually depolarizes via the funny current (If) until reaching threshold, where an AP is triggered.
  • Rate of depolarization (slope of If) determines heart rate; steeper slope = faster HR.
  • T-type Ca²⁺ channels mediate early depolarization; L-type Ca²⁺ channels cause the upstroke of the AP.
  • SA node depolarization is Ca²⁺-driven, unlike cardiac myocytes (which rely on Na⁺).
  • Reduced K⁺ permeability slows repolarization and speeds up depolarization, further increasing HR.

Autonomic Nervous System Modulation of SA Node

  • Modulates SA node pacemaker activity by altering the slope of the funny current (If).
  • Sympathetic activation (e.g., exercise) increases noradrenaline, stimulating β₁-adrenergic receptors, which raises cAMP, steepens depolarization slope, and increases heart rate.
  • Parasympathetic activation (via acetylcholine on muscarinic receptors) reduces cAMP, flattens the slope of the funny current, and slows heart rate.

Vagal Tone

  • Parasympathetic activity via the vagus nerve innervates the SA node and slows heart rate.
  • Sympathetic activation increases heart rate by increasing the firing frequency of the SA node.

Functional Syncytium

  • Cardiac myocytes are connected by low-resistance gap junctions, forming a functional syncytium.
  • Allows rapid, efficient spread of depolarization from cell to cell.

Cardiac Conduction System

  • Includes SA node, AV node, bundle of His, left and right bundle branches, and Purkinje fibers.
  • The action potential originates at the SA node, spreads to the AV node (where conduction slows to allow atrial contraction), then travels rapidly through the bundle of His, bundle branches, and Purkinje fibers to the ventricles.
  • Muscle tissue conducts more slowly than these specialized pathways.
  • Depolarization spreads from the ventricular apex upwards toward the base, producing a coordinated contraction that effectively ejects blood into the aorta and pulmonary artery.
  • Apex-to-base contraction follows atrial contraction and ensures efficient ventricular emptying.
  • The shape of the ventricular action potential is influenced by these conduction properties.
  • Contraction happens from apex (bottom) to base (top), following atrial contraction.

Electrocardiography (ECG)

  • Records the heart’s electrical activity using body-surface electrodes.
  • The standard setup uses three limb leads placed on the right arm, left arm, and left leg/rib, forming a triangle around the heart.
  • Electrical activity travels from negative to positive (e.g., RA to LA), and the heart’s position affects how this activity is detected.
  • Measures voltage differences caused by depolarization and repolarization moving through the myocardium.
  • If the wave moves toward a positive electrode, it shows as an upward (positive) deflection. If it moves away, it shows as a downward (negative) deflection.
  • ECG waveforms reflect the direction of these signals relative to the lead placement and the heart’s orientation in the chest.

Einthoven’s Triangle

  • The original ECG setup involved electrodes submerged in potassium chloride solution (a conducting liquid).
  • In modern ECGs, electrodes are placed on the chest, making direct contact with the skin using conductive gel.

Standard ECG Leads

  • A standard ECG consists of three limb leads (I, II, and III), forming Einthoven’s triangle.
  • What is typically thought of as a typical ECG trace is what is seen in lead II because the direction of the polarization of the lead aligns closely with the heart’s natural depolarization direction.

12-Lead ECG System

  • As depolarization moves across the heart, lead II shows a positive deflection when the wave travels in the same direction as the lead’s polarity (right arm → left leg).
  • If depolarization moves opposite to the lead’s direction, a negative deflection appears.
  • ECG deflections depend on whether the electrical wave moves toward or away from the positive electrode.

ECG Waveforms and Cardiac Activity

  • Atrial depolarization begins at the SA node, producing the P wave.
  • Since depolarization moves in the same direction as lead II, it creates a positive deflection. Lead III also shows a positive deflection but at a different angle. All three leads detect this upward deflection.

Ventricular Depolarization

  • Begins at the interventricular septum.
  • When the septum depolarizes, there is a negative deflection, producing the Q wave (not going in the same direction as polarization of lead II). In lead III, there would be a positive deflection.

QRS Complex

  • Reflects ventricular depolarization.
  • The depolarization wave moves upward along the ventricular walls, the direction of depolarization changes in relation to the lead, and this causes a negative deflection in the ECG, marking the end of the QRS complex.

Augmented Leads

  • Augmented leads are derived from leads I, II, and III.
  • aVR = - (Lead I + Lead II) / 2
  • aVL = (Lead I - Lead III) / 2
  • aVF = (Lead II + Lead III) / 2
  • An ECG typically uses 12 leads: three main leads (I, II, III), augmented leads (aVR, aVL, aVF), and six precordial leads placed on the chest.
  • These leads provide different perspectives, offering a comprehensive view of the heart's electrical activity from multiple angles. Each lead records slightly different information, contributing to a complete picture of the heart's electrical function.

Precordial Leads

  • Give a transverse (or axial) perspective of the heart’s electrical activity.

Typical ECG Pattern

  • Recorded in lead II, which shows the P-wave, QRS complex, and T-wave.
  • The P-wave corresponds to atrial depolarization, the QRS complex reflects ventricular depolarization, and the T-wave shows ventricular repolarization.

Relationship Between ECG and Ventricular Action Potential

  • If the ECG trace is superimposed onto the ventricular action potential, what you record in the action potential is essentially the ventricular depolarization.
  • The fast upstroke of the action potential aligns with the QRS complex, while repolarization corresponds to the T-wave.

PR and QT Intervals

  • Have normal ranges that help diagnose conditions.
  • A prolonged PR interval may indicate heart block.
  • A prolonged QT interval suggests long QT syndrome, which can be congenital or acquired and increases arrhythmia risk.
  • Some drugs require ECGs before use due to potential cardiac side effects.

Heart's Position and Axis Deviation

  • The heart's position in the chest affects the ECG's appearance. Abnormal positioning, such as hypertrophy, can shift the direction of depolarization, causing axis deviations.
  • Left axis deviation can cause negative deflections in leads II and III, while right axis deviation can alter deflections in leads II, III, and I. These deviations can be normal or indicate heart disease. The ECG can help assess the heart's position.

Sinus Arrhythmia

  • A normal heart rhythm variation, where the heart rate increases and decreases with respiration.
  • Caused by changes in chest pressure and the interaction between the respiratory and cardiovascular centers in the brainstem, which modulate vagal tone.

Heart (AV) Block

  • Disease in the conduction system can lead to blocks, such as AV block.
  • First-degree AV block is characterized by a prolonged PR interval, indicating delayed conduction through the AV node (slowed down conduction).
  • Disease in the AV node leads to slower depolarization.
  • If the conduction delay worsens, leading to the dropping of the QRS complex, this could suggest a higher-degree AV block, which is more severe and can disrupt the heart's rhythm.

Cardiac Channelopathies

  • Disorders caused by abnormalities in ion channel proteins, affecting the heart’s electrical activity.
  • Long QT syndrome is a congenital condition where the QT interval on an ECG is prolonged, indicating delayed ventricular repolarization. This delay, caused by mutations in ion channel genes (like potassium or sodium channels), increases the risk of arrhythmias.
  • Consequences include syncope (fainting), seizures (from abnormal brain activity), sudden cardiac death, and Torsades de Pointes, a dangerous arrhythmia associated with long QT syndrome.

Ventricular Myocyte Action Potential and Channelopathies

  • Includes:
    • INa (sodium current): Rapid depolarization
    • Ica-L (L-type calcium current): Plateau phase
    • IKr, IKs, IK1 (potassium currents): Repolarization

Mutations and Syndromes

  • The KvLQT1 + minK complex forms the slow delayed rectifier potassium current (IKs), involved in repolarization. Mutations in KCNQ1 cause LQTS type 1 (LQT1), leading to prolonged repolarization and risk of Torsades de Pointes. LQT1 is triggered by exercise, especially swimming. LQTS results from delayed potassium currents or increased late sodium/calcium currents.
  • Brugada Syndrome (BrS) involves INa defects (mutations in SCN5A, Nav1.5), causing activation failure, loss of action potential dome, and arrhythmias. It predisposes to sudden cardiac death, especially during sleep/fever.
  • CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) is due to RYR2 mutations, causing calcium leakage and exercise-induced arrhythmias. Normal resting ECG, but arrhythmias triggered by stress/exercise. Treated with beta-blockers (e.g., propranolol).

QT Interval

  • A prolonged QT (QTc) indicates risk of arrhythmias, with drug-induced LQTS (e.g., antiarrhythmics, antibiotics, antipsychotics).
    V1-V3: Right ventricular issues (Brugada, RV hypertrophy, WPW). V5-V6: Left ventricular issues.

Genetic Mutations and Arrhythmias

  • SCN5A (Nav1.5): Linked to LQTS, Brugada Syndrome, and conduction defects.
  • Potassium channels: Mutations in KCNH2 (HERG), KCNQ1, KCNE1 cause LQTS subtypes (LQT1, LQT2, LQT5), affecting repolarization and prolonging the QT interval, increasing the risk of Torsades de Pointes and sudden cardiac death.
  • KCNE3 and KCND3: Linked to Brugada Syndrome (phase 1 repolarization).
  • Calcium handling defects (e.g., RYR2): Seen in LQTS and CPVT, causing abnormal Ca²⁺ release, promoting arrhythmias.
  • KCNQ1: Encodes the slow delayed rectifier potassium current (IKs), mutations cause LQT1 (prolonged repolarization).
  • KCNE1: Modulates KCNQ1, mutations linked to LQT5, typically milder than LQT1.
  • KCNH2 and KCNE2 mutations: Linked to LQTS and SIDS (sudden infant death syndrome), emphasizing genetic screening for arrhythmic risk.

Hyperkalemia

  • Normal: 3.5-5mM

  • >5.5mM

  • >6.5mM

  • 10mM

  • 10-12mM

  • 12mM

  • EK = (RT / zF) * ln([K^+]o / [K^+]_i)

Effects of Hyperkalemia

  • Depolarizes the myocytes, which interferes with the generation and propagation of the action potential.

Physiological Context of Potassium

  • Potassium is mainly intracellular, maintained by the Na+/K+ ATPase pump.
  • Hyperkalemia (excess potassium in the blood) causes:
    • Prolonged depolarization: Higher extracellular K+ makes it harder for cells to repolarize.
    • ECG changes: QRS complex widens; T waves become tall and peaked; Conduction slows.
    • Severe hyperkalemia: Leads to disappearance of P waves and a sinusoidal ECG shape, signaling impending ventricular fibrillation or asystole (cardiac arrest).

Hypokalemia and Drug-Induced Effects

  • Self-medication for Covid-19 using chloroquine phosphate (fish tank cleaner).
  • Licorice overdose (Glycyrrhizin/glycyrrhizic acid):
    • Hypokalemia.
    • Arrhythmias-QT prolongation.
    • Hypertension.
    • Inhibits renal 11β-hydroxysteroid dehydrogenase (activation of MRs by excess cortisol)-pseudoaldosteronism.
  • Chloroquine & Hydroxychloroquine: Activate inward rectifier potassium channels (Kir) in cardiac cells, leading to hypokalemia. Hypokalemia increases the risk of QT prolongation and Torsades de Pointes (TdP).
  • Licorice overdose (glycyrrhizin/glycyrrhizic acid) inhibits 11β-HSD2, causing cortisol accumulation and overstimulation of mineralocorticoid receptors (MRs), leading to sodium retention, potassium loss, and hypertension. Severe potassium depletion increases the risk of ventricular arrhythmias and QT prolongation.