15.3 Cardiac Electrophysiology, ECG & Hemodynamics

15.3 Cardiac Electrophysiology, ECG & Hemodynamics

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Cardiac Action Potentials: Fast-Response vs. Slow-Response

The myocardium is an electromechanical syncytium composed of two functionally distinct categories of excitable tissue: fast-response working myocytes (atrial and ventricular cardiomyocytes, Purkinje conduction fibers) and slow-response pacemaker cells (sinoatrial [SA] node and atrioventricular [AV] node). These two cellular populations exhibit fundamentally different electrophysiological profiles, ion channel expressions, and pharmacological responses.

               Cardiac Action Potentials: Fast vs. Slow Response
               
    FAST RESPONSE (Ventricular Myocyte)       SLOW RESPONSE (SA Node Pacemaker)
    ───────────────────────────────────       ─────────────────────────────────
    Voltage (mV)                              Voltage (mV)
        ▲                                         ▲
    +20 ┼      Phase 1 Notch                      │
        │        /\  Phase 2 Plateau (ICa,L)      │
      0 ┼───────/──\══════════════\               │           Phase 0 (ICa,L)
        │      /                   \              │             /\
    -40 ┼     / Phase 0             \ Phase 3 -40 ┼────────────/──\──────────────
        │    /  (INa via             \            │ Threshold /    \ Phase 3
    -60 ┼   /    NaV1.5)              \       -60 ┼───\______/      \_____/
        │  /                           \          │   Max Diastolic  Phase 4
    -85 ┼─/─────────────────────────────\─────    │   Potential      (If current)
        │ Phase 4 (IK1 resting potential)         │
        └─────────────────────────────────►       └─────────────────────────►
                      Time (ms)                                 Time (ms)

1. Fast-Response Action Potential (Ventricular & Purkinje Cells)

The working ventricular cardiomyocyte maintains a deeply negative resting potential ($-85\text{ to } -90\text{ mV}$) and generates a long-duration ($200-300\text{ ms}$) action potential divided into five distinct phases:

• Phase 0: Rapid Upstroke (Depolarization):
  • Triggered when an electrical impulse conducted via gap junctions depolarizes the sarcolemma to threshold ($-70\text{ mV}$).
  • Voltage-gated cardiac sodium channels ($Na_V1.5$) snap open, producing a massive inward sodium current ($I_{Na}$).
  • Exhibits an extraordinary upstroke velocity ($dV/dt_{max} \approx 200 - 400\text{ V/s}$), rapidly inverting membrane polarity to an overshoot peak of $+20\text{ to } +30\text{ mV}$.
  • Pharmacology: Target of Class I antiarrhythmic drugs (Class IA: quinidine, procainamide; Class IB: lidocaine, mexiletine; Class IC: flecainide, propafenone).
• Phase 1: Initial Rapid Repolarization (The Notch):
  • Rapid inactivation of $Na_V1.5$ channels halts inward $I_{Na}$.
  • Transient opening of voltage-gated transient outward potassium channels ($I_{to1}$) and inward chloride current ($I_{to2}$) produces a brief outward repolarizing current, creating the characteristic "notch" on the waveform.
• Phase 2: The Plateau Phase (The Hallmark of Cardiac Muscle):
  • Lasts $200 - 300\text{ ms}$, during which the membrane potential remains relatively constant near $0\text{ mV}$.
  • Maintained by a precise thermodynamic equilibrium between inward depolarizing current through voltage-gated L-type calcium channels ($Ca_V1.2$, $I_{Ca,L}$) and outward repolarizing current through delayed rectifier potassium channels ($I_{Ks}, I_{Kr}$).
  • Calcium entering through L-type channels triggers Calcium-Induced Calcium Release (CICR) from the sarcoplasmic reticulum ($SR$) via Ryanodine Receptor 2 (RyR2), initiating cross-bridge cycling and systolic contraction.
  • Crucial Physiological Function: The prolonged plateau extends the Absolute Refractory Period (ARP) throughout the entire duration of mechanical contraction. Consequently, cardiac muscle cannot be tetanized, ensuring that the heart rhythmically contracts and relaxes to allow ventricular filling between beats.
• Phase 3: Rapid Final Repolarization:
  • Inactivation of L-type $Ca^{2+}$ channels halts inward $I_{Ca,L}$.
  • Outward delayed rectifier potassium channels—rapidly activating ($I_{Kr}$) and slowly activating ($I_{Ks}$)—predominate, driving rapid potassium efflux ($I_K$) that repolarizes the membrane back to negative resting levels.
  • Pharmacology: Blockade of $I_{Kr}$ by Class III antiarrhythmics (amiodarone, sotalol, dofetilide) or non-cardiac drugs prolongs Phase 3, widening the ECG QT interval.
• Phase 4: Resting Membrane Potential:
  • Maintained at a stable $-85\text{ to } -90\text{ mV}$ by the inward rectifier potassium current ($I_{K1}$), which remains open at negative voltages to clamp $V_m$ close to $E_K$. The $Na^+/K^+$ ATPase and NCX sustain background ion gradients.

2. Slow-Response Action Potential (SA & AV Nodal Pacemaker Cells)

Pacemaker tissue exhibits intrinsic automaticity—the capacity to generate spontaneous, rhythmic action potentials without external neurohumoral input. Pacemaker cells possess three cardinal electrophysiological differences:

1. They lack a stable resting membrane potential during Phase 4.
2. They lack functional fast $Na_V1.5$ channels (inactivated by chronic partial depolarization) and inward rectifier $I_{K1}$ channels.
3. Phase 1 and Phase 2 are completely absent.

• Phase 4: Spontaneous Diastolic Depolarization (Pacemaker Potential):
  • At the end of repolarization, the membrane reaches its maximum diastolic potential ($-60\text{ mV}$).
  • This hyperpolarization activates Hyperpolarization-activated Cyclic Nucleotide-gated channels (HCN4), which carry an inward, depolarizing mixed cation current dominated by sodium, termed the "Funny" Current ($I_f$) (so named because it is uniquely activated by hyperpolarization rather than depolarization).
  • As $I_f$ slowly depolarizes the membrane, outward $K^+$ current decays, and transient T-type calcium channels ($I_{Ca,T}$) open, pushing the voltage upward toward threshold ($-40\text{ mV}$).
  • Autonomic Regulation:
    • Sympathetic Stimulation: Norepinephrine and epinephrine bind $\beta_1$-adrenergic receptors, coupling to $G_s$ proteins to stimulate adenylyl cyclase, elevating intracellular cyclic AMP (cAMP). cAMP directly binds HCN channels, increasing $I_f$ open probability. This steepens the slope of Phase 4, reaching threshold faster and increasing heart rate (positive chronotropy).
    • Parasympathetic (Vagal) Stimulation: Acetylcholine binds muscarinic $M_2$ receptors, coupling to $G_i$ proteins. This inhibits adenylyl cyclase (lowering cAMP) and directly opens acetylcholine-activated potassium channels ($I_{K,ACh}$) via liberated $G_{\beta\gamma}$ subunits. The membrane hyperpolarizes and the Phase 4 slope flattens, taking longer to reach threshold and slowing heart rate (negative chronotropy).
• Phase 0: Slow Upstroke (Depolarization):
  • Once threshold ($-40\text{ mV}$) is reached, depolarization is mediated entirely by inward calcium influx through L-type calcium channels ($I_{Ca,L}$).
  • Because L-type calcium channels open far more sluggishly than fast sodium channels, the upstroke velocity is very slow ($dV/dt_{max} \approx 2 - 10\text{ V/s}$).
  • Clinical Significance: This sluggish upstroke in the AV node accounts for the AV nodal conduction delay (0.12–0.20 seconds), which allows the atria sufficient time to complete mechanical contraction and empty blood into the ventricles before ventricular systole commences.
• Phase 3: Repolarization:
  • Inactivation of L-type $Ca^{2+}$ channels coupled with the opening of voltage-gated delayed rectifier $K^+$ channels ($I_K$) repolarizes the pacemaker cell back to its maximum diastolic potential ($-60\text{ mV}$), resetting the HCN channels to initiate the next cycle.

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Surface Electrocardiography: Waves, Intervals & Clinical Pathologies

The 12-lead surface electrocardiogram (ECG) records the spatial and temporal summation of extracellular electrical potentials generated by the heart, calibrated at a standard paper speed of $25\text{ mm/s}$ ($1\text{ small box} = 0.04\text{ s}$; $1\text{ large box} = 0.20\text{ s}$) and voltage calibration of $10\text{ mm/mV}$ ($1\text{ small box} = 0.1\text{ mV}$; $1\text{ large box} = 0.5\text{ mV}$).

                      The Normal Surface ECG Complex
                      
    Voltage (mV)
         ▲
     1.0 ┼                       R Wave
         │                         /\
     0.5 ┼           P Wave       /  \                T Wave
         │            ┌──┐       /    \                ┌───┐
       0 ┼────────────┘  └───┐  /      \   ST Segment  │   │
         │                   │ /        \──────────────┘   └────────►
    -0.5 ┼                   └/          \                          Time
         │                  Q Wave        \ S Wave
         └──────────────────────────────────────────────────────────
                 ◄─ PR ──►   ◄── QRS ───►  ◄────── QT Interval ─────►
                 (0.12-0.20s)  (<0.12s)          (<0.44s)

ECG Waves, Complexes & Intervals

1. P Wave:
   • Represents atrial depolarization spreading from the SA node across the right and left atria.
   • Normal duration: $<0.12\text{ seconds}$ (<3 small boxes); normal amplitude: $<2.5\text{ mm}$ in lead II.
   • Pathology: Tall, peaked P waves ($>2.5\text{ mm}$) indicate right atrial enlargement (P-pulmonale, seen in chronic cor pulmonale); broad, notched, bifid P waves ($>0.12\text{ s}$) in lead II indicate left atrial enlargement (P-mitrale, seen in severe mitral stenosis).
2. PR Interval:
   • Measured from the onset of the P wave to the onset of the QRS complex.
   • Represents the total time required for SA nodal discharge, atrial depolarization, and the critical physiological conduction delay through the AV node, bundle of His, and bundle branches.
   • Normal duration: $0.12\text{ to } 0.20\text{ seconds}$ (3 to 5 small boxes).
   • Pathology:
     • Prolonged PR ($>0.20\text{ s}$): First-Degree AV Block (delayed AV nodal conduction, benign).
     • Short PR ($<0.12\text{ s}$) with a slurred QRS upstroke (Delta wave): Wolff-Parkinson-White (WPW) Syndrome, caused by an accessory antegrade atrioventricular conduction pathway (Bundle of Kent) that bypasses the normal AV nodal delay.
3. QRS Complex:
   • Represents ventricular depolarization (atrial repolarization occurs simultaneously but is completely obscured by the massive electrical vector of the ventricles).
   • Normal duration: $<0.12\text{ seconds}$ (<3 small boxes).
   • Pathology: Widened QRS complex ($>0.12\text{ s}$) indicates aberrant or slowed intraventricular conduction: Right Bundle Branch Block (RBBB) (rsR' "rabbit ears" in V1–V3), Left Bundle Branch Block (LBBB) (broad notched R waves in I, aVL, V5–V6), or ectopic ventricular activation (premature ventricular complexes, ventricular tachycardia).
4. ST Segment:
   • Extends from the end of the S wave (the J-point) to the beginning of the T wave.
   • Normally flat and isoelectric, corresponding to Phase 2 plateau of ventricular action potentials when all ventricular myocytes are uniformly depolarized.
   • Pathology:
     • ST-Segment Elevation: Signifies acute transmural myocardial ischemia / infarction (STEMI) or acute pericarditis (diffuse saddle-shaped elevation with PR depression).
     • ST-Segment Depression: Indicates subendocardial ischemia (NSTEMI, unstable angina) or digitalis effect ("scooped" concave ST depression).
5. T Wave:
   • Represents ventricular repolarization (Phase 3). Asymmetric with a gradual upslope and rapid downslope.
   • Pathology: Tall, narrow, "tented" or peaked T waves represent early hyperkalemia; flattened T waves with prominent U waves (repolarization of Purkinje fibers or papillary muscles) represent hypokalemia.
6. QT Interval & Rate-Corrected QTc:
   • Measured from the beginning of the Q wave to the end of the T wave; represents the total duration of ventricular electrical systole (depolarization plus repolarization).
   • Because the QT interval naturally shortens at faster heart rates and lengthens at slower rates, it must be normalized using Bazett's Formula:

$QTc = \frac{QT}{\sqrt{RR}}$

(Where $QT$ and $RR$ intervals are measured in seconds).

• Normal QTc values: $<440\text{ ms}$ in adult males; $<460\text{ ms}$ in adult females.
• Prolonged QTc ($>480 - 500\text{ ms}$) permits early afterdepolarizations (EADs) during Phase 2/3 to trigger a lethal polymorphic ventricular tachycardia with twisting of QRS peaks around the isoelectric line: Torsades de Pointes.

The Cardiac Cycle, Pressure-Volume Loops & Heart Sounds

The cardiac cycle describes the sequence of alternating electrical, pressure, volume, and valvular events occurring during a single complete heartbeat, divided into systole (ventricular contraction and ejection) and diastole (ventricular relaxation and filling).

Phases of the Wiggers Cardiac Cycle

                  Left Ventricular Pressure-Volume (PV) Loop
                  
    Left Ventricular
    Pressure (mmHg)
         ▲
     120 ┼                  Aortic Valve Closes (ESV)
         │                 ┌────────────────┐
         │                 │                │
      80 ┼  Aortic Valve   │                │ Isovolumetric
         │  Opens          │  EJECTION      │ Relaxation
         │                 │                │ (S2: A2 then P2)
      20 ┼  Isovolumetric  │                │
         │  Contraction    │   DIASTOLIC    │ Mitral Valve Opens
       0 ┼──(S1: M1 then T1)────────────────┴───────────────►
         │                 │                │               Left Ventricular
         0                 50 (ESV)         120 (EDV)       Volume (mL)
                           ◄──── SV = 70 mL ──►

1. Atrial Systole: Corresponds to the P wave. Atria contract to pump the final $10 - 20\%$ of blood into the relaxed ventricles (the "atrial kick"). Ventricular volume reaches its maximum: End-Diastolic Volume ($EDV \approx 120\text{ mL}$) at an End-Diastolic Pressure ($EDP \approx 8 - 12\text{ mmHg}$). Produces the $a$-wave on jugular venous pulse (JVP) tracings.
2. Isovolumetric Ventricular Contraction: Ventricular depolarization (QRS complex) triggers contraction. Left ventricular pressure surges immediately above left atrial pressure ($>10\text{ mmHg}$), snapping the mitral valve closed (generating the first heart sound, S1). Because aortic pressure ($80\text{ mmHg}$) still exceeds ventricular pressure, the aortic valve remains closed. All four cardiac valves are closed. Left ventricular pressure escalates precipitously from $10$ to $80\text{ mmHg}$ with zero change in blood volume.
3. Rapid Ventricular Ejection: Ventricular pressure exceeds aortic pressure ($>80\text{ mmHg}$); the aortic valve bursts open. Ventricular blood is ejected forcefully into the ascending aorta, peaking at $120\text{ mmHg}$.
4. Reduced Ventricular Ejection: Repolarization begins (T wave). Ventricular pressure begins to decline as outflow slows, but aortic run-off maintains forward momentum.
5. Isovolumetric Ventricular Relaxation: Ventricular pressure falls below aortic pressure; backward blood flow catches the aortic valve cusps, snapping the aortic valve closed (generating the second heart sound, S2). Valve closure produces a transient pressure rebound on the aortic pressure tracing termed the dicrotic notch (incisura). Ventricular pressure plunges rapidly from $100$ down to $10\text{ mmHg}$ with all four valves closed and zero change in blood volume. The residual volume remaining in the ventricle is the End-Systolic Volume ($ESV \approx 50\text{ mL}$).
6. Rapid Ventricular Filling: Ventricular pressure drops below atrial pressure; the mitral valve opens. Blood accumulated in the left atrium cascades passively into the relaxed ventricle, accounting for roughly $70 - 80\%$ of total ventricular filling.
7. Reduced Ventricular Filling (Diastasis): Passive filling decelerates as ventricular pressure approaches atrial pressure, awaiting the next atrial contraction.

Heart Sounds & Murmur Mechanics

• First Heart Sound (S1):
  • Produced by the sudden deceleration of blood and closure of the atrioventricular (mitral and tricuspid) valves at the onset of isovolumetric contraction. Mitral closure ($M_1$) slightly precedes tricuspid closure ($T_1$). Best auscultated at the cardiac apex (fifth intercostal space, midclavicular line).
• Second Heart Sound (S2):
  • Produced by closure of the semilunar (aortic and pulmonic) valves at the onset of isovolumetric relaxation. Composed of aortic ($A_2$) and pulmonic ($P_2$) components. Best heard at the second right (aortic) and second left (pulmonic) intercostal spaces.
  • Physiological Splitting of S2: During inspiration, negative intrathoracic pressure expands pulmonary vascular capacitance, delaying pulmonic ejection and delaying $P_2$ closure, while transiently reducing left ventricular venous return, accelerating $A_2$ closure. As a result, $A_2$ and $P_2$ audibly separate during inspiration and fuse into a single sound during expiration.
• Third Heart Sound (S3 Gallop):
  • A low-pitched, early diastolic sound occurring during the rapid ventricular filling phase, immediately following S2 (cadence: "Ken-tuck-y").
  • Produced by the abrupt deceleration of inflow into a volume-overloaded, highly compliant, or dilated ventricle.
  • Clinical Significance: Normal in healthy children, well-trained endurance athletes, and third-trimester pregnant females. In adults $>40$ years old, S3 is a sensitive, highly specific hallmark of systolic congestive heart failure (dilated cardiomyopathy, reduced ejection fraction) or severe mitral regurgitation.
• Fourth Heart Sound (S4 Gallop):
  • A low-pitched, late diastolic sound occurring during atrial systole, immediately preceding S1 (cadence: "Ten-nes-see").
  • Produced by forceful atrial contraction pumping blood into a stiff, non-compliant, hypertrophied ventricle ("atrial kick against a stiff wall").
  • Clinical Significance: Always pathological. Highly characteristic of left ventricular concentric hypertrophy secondary to chronic systemic hypertension, severe aortic valve stenosis, or hypertrophic cardiomyopathy (HCM). S4 can never occur in atrial fibrillation because coordinated atrial contraction is absent.

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Cardiac Output Determinants: Preload, Afterload & Inotropy

Cardiac Output ($CO$) is the total volume of blood pumped by each ventricle per unit time (expressed in $\text{L/min}$):

$CO = HR \times SV$

Where:

• $HR$ is Heart Rate (normal resting: $60 - 100\text{ beats/min}$).
• $SV$ is Stroke Volume ($EDV - ESV$, normal resting: $\approx 70\text{ mL}$).
• Normal resting Cardiac Output in a $70\text{-kg}$ adult is $4.5 - 5.5\text{ L/min}$.
• Cardiac Index ($CI$): Normalizes $CO$ to Body Surface Area ($BSA$): $CI = CO / BSA$ (normal: $2.5 - 4.0\text{ L/min}/\text{m}^2$).

The Fick Principle

The gold-standard physiological technique for calculating cardiac output non-invasively relies on Adolf Fick's conservation of mass principle, stating that the total uptake of a substance (oxygen) by an organ (the lungs) equals the blood flow through the organ multiplied by the arteriovenous concentration difference:

$CO = \frac{\text{Total Body Oxygen Consumption } (\dot{V}_{O2})}{[C_a O_2] - [C_v O_2]}$

Where:

• $\dot{V}_{O2}$ is whole-body oxygen consumption measured via spirometry (normally $\approx 250\text{ mL } O_2/\text{min}$).
• $[C_a O_2]$ is arterial oxygen content (normally $\approx 20\text{ mL } O_2/\text{dL} = 200\text{ mL } O_2/\text{L}$).
• $[C_v O_2]$ is mixed venous oxygen content sampled from a pulmonary arterial catheter (normally $\approx 15\text{ mL } O_2/\text{dL} = 150\text{ mL } O_2/\text{L}$).
• Applying typical resting values: $CO = 250 / (200 - 150) = 250 / 50 = 5.0\text{ L/min}$.

Determinants of Stroke Volume: Preload, Afterload & Contractility

                     Determinants of Left Ventricular Stroke Volume
                     
            PRELOAD                               AFTERLOAD
     (End-Diastolic Volume)                (Systemic Vascular Resistance)
               │                                         │
               ▼ AUGMENTS                                ▼ OPPOSES
      ┌────────────────────────────────────────────────────────┐
      │                 STROKE VOLUME (SV)                     │
      │               Normal: 70 mL per beat                   │
      └────────────────────────────────────────────────────────┘
                               ▲ AUGMENTS
                               │
                         CONTRACTILITY
                           (Inotropy)
                    (Intracellular Free Ca2+)

1. Preload (End-Diastolic Stretch)

• Preload represents the resting tension or stretch experienced by the cardiomyocyte sarcolemma at the end of diastole, immediately prior to contraction, clinically estimated by End-Diastolic Volume ($EDV$) or End-Diastolic Pressure ($EDP$).
• The Frank-Starling Law of the Heart: The intrinsic property of cardiac muscle whereby increasing resting fiber length (ventricular filling) enhances the force of subsequent systolic contraction, increasing stroke volume. Mechanistically:
  1. Stretching increases sarcomere length from its resting sub-optimal length ($1.8\,\mu\text{m}$) toward the optimal mechanical plateau ($2.2\,\mu\text{m}$), maximizing the steric orientation and overlap between actin active sites and myosin cross-bridges.
  2. Increased stretch enhances the calcium sensitivity of Troponin C, so that a given influx of calcium elicits greater actomyosin cross-bridge cycling.
• Clinically increased by: intravenous crystalloid volume expansion, sympathetic venoconstriction (elevating venous return), and bradycardia (prolonging diastolic filling time).

2. Afterload (Impedance to Ejection)

• Afterload represents the physical resistance or load against which the ventricle must exert tension to eject stroke volume into the arterial circulation, primarily determined by Mean Arterial Pressure ($MAP$) and Systemic Vascular Resistance ($SVR$).
• Governed by the Law of Laplace for a Spherical Chamber:

$\text{Myocardial Wall Stress } (\sigma) = \frac{P \cdot r}{2h}$

Where:

• $P$ is intraventricular systolic pressure.
• $r$ is internal ventricular radius (chamber volume).
• $h$ is ventricular wall thickness.
• Clinical Adaptation: In chronic essential hypertension or aortic stenosis, sustained elevated systolic pressure ($P$) drastically increases afterload wall stress. To normalize wall stress, the myocardium synthesizes new sarcomeres in parallel, increasing wall thickness ($h$) to produce concentric left ventricular hypertrophy (LVH). Conversely, in chronic volume overload (mitral regurgitation, dilated cardiomyopathy), increased radius ($r$) prompts sarcomere assembly in series, producing eccentric hypertrophy.

3. Contractility (Inotropic State)

• Contractility represents the intrinsic, load-independent mechanical vigor of myocardial shortening at any given preload and afterload.
• Contractility is governed directly by the magnitude of the free intracellular calcium transient ($[Ca^{2+}]_i$) reached during Phase 2 of the cardiac action potential.
• Ejection Fraction ($EF$): The primary clinical measure of contractile function:

$EF = \frac{SV}{EDV} = \frac{EDV - ESV}{EDV} \times 100\%$

• Normal resting Ejection Fraction is $55\% - 70\%$ ($EF < 40\%$ defines systolic heart failure with reduced ejection fraction [HFrEF]).
• Factors Increasing Contractility (Positive Inotropes): Sympathetic $\beta_1$-adrenergic stimulation (epinephrine, norepinephrine, dobutamine via PKA phosphorylation of phospholamban and L-type channels), cardiac glycosides (digoxin), and hypercalcemia. Shift the Frank-Starling ventricular function curve upward and to the left.
• Factors Decreasing Contractility (Negative Inotropes): $\beta$-blockers (metoprolol, atenolol), non-dihydropyridine calcium channel blockers (verapamil, diltiazem), acute metabolic acidosis ($pH < 7.2$), myocardial ischemia, and hypercapnia. Shift the Frank-Starling curve downward and to the right.