3.1 Cardiac Electrophysiology, the Cardiac Cycle & the Heart as a Pump

Why this area matters

The 2025 Physiology TOS gives the cardiovascular system 17 items, tied with neurophysiology for the largest share. It lists "electrophysiology of the heart, the cardiac cycle, the heart as a pump" before the circulation topics covered in the next section. These mechanisms come back in Medicine (arrhythmias, heart failure), Pharmacology (antiarrhythmics, inotropes) and Pediatrics (murmurs).

Cardiac action potentials

Ventricular and atrial myocytes and Purkinje fibers ("fast response"):

The plateau provides the trigger calcium for contraction. It also makes the effective refractory period last almost as long as contraction, so cardiac muscle cannot be tetanized.

SA and AV nodal cells ("slow response"): there is no fast Na+ upstroke. Phase 0 is carried by L-type Ca2+ current, which is why nodal conduction is slowed by calcium-channel blockers. Phase 4 is a spontaneous diastolic depolarization driven by the funny current (If) through HCN channels and by T-type Ca2+ current. The SA node fires fastest, about 60 to 100 times a minute, so it sets the rhythm. The AV node fires at 40 to 60 and the Purkinje system at 20 to 40, which explains junctional and ventricular escape rhythms.

Autonomic effects:

• Sympathetic beta-1 stimulation (cAMP) steepens phase 4, raising heart rate, and speeds AV conduction.
• Vagal acetylcholine acting on M2 receptors opens K+ channels and reduces If and Ca2+ current. Phase 4 flattens, the cell hyperpolarizes, the heart rate falls and the PR interval lengthens.

Conduction and the ECG

Conduction runs from the SA node through the atrial muscle to the AV node, then the bundle of His, the bundle branches and the Purkinje network. The AV node is the slowest segment (about 0.05 m/s). Its delay lets the atria empty before the ventricles contract. Purkinje fibers are the fastest (about 1.5 to 4 m/s), so the ventricles depolarize almost at once.

Atrial repolarization is buried in the QRS. Hypokalemia flattens T waves and produces U waves. Hyperkalemia peaks T waves, widens the QRS and can end in a sine-wave pattern.

The Cardiac Cycle, Wiggers Diagram & Heart Sounds

The cardiac cycle integrates electrical conduction (ECG), intracardiac pressures, ventricular volume alterations, and valve closures.

Phases of the Cardiac Cycle

1. Ventricular Systole:
   • Isovolumetric Contraction: Begins with ventricular depolarization (QRS complex). Left ventricular (LV) pressure exceeds left atrial (LA) pressure, causing abrupt closure of the mitral valve (generating the $M_1$ component of the First Heart Sound, $S_1$). Because aortic diastolic pressure ($\sim 80\text{ mmHg}$) exceeds LV pressure, all four cardiac valves are closed. Ventricular pressure rises precipitously from $\sim 8\text{ mmHg}$ to $80\text{ mmHg}$ without any change in ventricular volume (End-Diastolic Volume, EDV $\approx 120\text{ mL}$).
   • Rapid Ventricular Ejection: LV pressure exceeds aortic pressure ($\sim 80\text{ mmHg}$), forcing the aortic valve open. Ventricular volume plummets rapidly as blood is ejected into the aorta. Peak LV and aortic systolic pressures reach $\sim 120\text{ mmHg}$.
   • Reduced Ventricular Ejection: Ventricular repolarization (T wave on ECG) begins. Ventricular pressure and aortic pressure begin to decline while ejection decelerates.
2. Ventricular Diastole:
   • Isovolumetric Relaxation: Ventricular pressure falls below aortic pressure. Backflow of blood catches the aortic valve cusps, snapping them closed (generating the $A_2$ component of the Second Heart Sound, $S_2$). This produces a transient incisura (dicrotic notch) on the aortic pressure tracing. All valves remain closed while LV pressure plunges toward zero with volume unchanged at its minimum (End-Systolic Volume, ESV $\approx 50\text{ mL}$).
   • Rapid Ventricular Filling: LV pressure drops below left atrial pressure, causing the mitral valve to open. Inflow of blood is passive and rapid, accounting for roughly 70% to 80% of total ventricular filling during early diastole.
   • Reduced Ventricular Filling (Diastasis): Passive ventricular filling slows as ventricular compliance limits further rapid inflow.
   • Atrial Systole ("Atrial Kick"): Coincides with the P wave on the ECG. Atrial contraction forces an additional 10% to 20% of stroke volume into the relaxed ventricle (up to 30% to 40% in elderly patients with noncompliant, hypertrophied ventricles).

Auscultation & Heart Sounds

• $S_1$ (First Heart Sound): Caused by closure of the atrioventricular (mitral and tricuspid) valves at the onset of ventricular systole. Loudest at the cardiac apex. Mitral closure ($M_1$) precedes tricuspid closure ($T_1$).
• $S_2$ (Second Heart Sound): Caused by closure of the semilunar (aortic and pulmonic) valves at the onset of ventricular diastole. Loudest at the left upper sternal border. Aortic closure ($A_2$) normally precedes pulmonic closure ($P_2$).
• Physiological Splitting of $S_2$: During inspiration, negative intrathoracic pressure increases venous return to the right heart, delaying pulmonic valve closure ($P_2$). Simultaneously, increased pulmonary vascular capacitance temporarily pools blood in the lungs, decreasing venous return to the left atrium, accelerating aortic valve closure ($A_2$). Thus, the $A_2\text{--}P_2$ split widens on inspiration and merges on expiration.
• Pathological $S_2$ Splitting Patterns:
  • Wide Splitting: Seen in right bundle branch block (RBBB) or pulmonic stenosis. Delayed electrical activation or delayed mechanical emptying of the right ventricle delays $P_2$, exaggerating normal inspiratory splitting.
  • Fixed Splitting: Diagnostic hallmark of Atrial Septal Defect (ASD). Left-to-right interatrial shunting causes persistent volume overload of the right heart across both respiratory phases. The split between $A_2$ and $P_2$ remains wide and invariant during inspiration and expiration.
  • Paradoxical (Reversed) Splitting: Seen in left bundle branch block (LBBB) or severe aortic stenosis. Left ventricular ejection is delayed so profoundly that $A_2$ occurs after $P_2$. On inspiration, delayed $P_2$ moves closer to $A_2$, narrowing the split; on expiration, $P_2$ moves earlier, widening the split.
• $S_3$ (Third Heart Sound): Low-frequency sound in early diastole during rapid ventricular filling. Caused by blood rushing into a volume-overloaded, compliant, or dilated ventricle. Normal in children, healthy young adults, and third-trimester pregnancy. Pathological in adults over 40 years, indicating systolic heart failure, dilated cardiomyopathy, or severe mitral regurgitation.
• $S_4$ (Fourth Heart Sound): Low-frequency sound in late diastole coinciding with atrial contraction ("atrial kick"). Caused by blood forced into a stiff, noncompliant ventricle. Always pathological in adults. Associated with concentric left ventricular hypertrophy secondary to chronic systemic hypertension, severe aortic stenosis, or hypertrophic cardiomyopathy.

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Ventricular Pressure-Volume Loops & Frank-Starling Law

The left ventricular Pressure-Volume (PV) loop plots intraventricular pressure against volume over a single cardiac cycle.

Cardinal Landmarks of the PV Loop

• Point A: Mitral valve opens (end of isovolumetric relaxation; LV pressure $\sim 5\text{ mmHg}$, volume $\sim 50\text{ mL}$).
• Segment A $\rightarrow$ B: Diastolic ventricular filling along the passive End-Diastolic Pressure-Volume Relationship (EDPVR) curve.
• Point B: Mitral valve closes at the onset of systole. Volume at this point is the End-Diastolic Volume (EDV $\approx 120\text{ mL}$).
• Segment B $\rightarrow$ C: Isovolumetric Contraction. Pressure rises with volume constant.
• Point C: Aortic valve opens when LV pressure exceeds aortic diastolic pressure ($\sim 80\text{ mmHg}$).
• Segment C $\rightarrow$ D: Ventricular ejection into the aorta.
• Point D: Aortic valve closes. Volume at this point is the End-Systolic Volume (ESV $\approx 50\text{ mL}$). The line connecting the origin through Point D is the End-Systolic Pressure-Volume Relationship (ESPVR), whose slope represents myocardial contractility (inotropy).
• Segment D $\rightarrow$ A: Isovolumetric Relaxation. Pressure drops vertically with volume constant at ESV.

Core Hemodynamic Calculations

$\text{Stroke Volume (SV)} = \text{EDV} - \text{ESV} \approx 120 - 50 = 70\text{ mL}$

$\text{Ejection Fraction (EF)} = \frac{\text{SV}}{\text{EDV}} \times 100\% = \frac{70}{120} \times 100\% \approx 58\% \quad (\text{Normal: } 55\%\text{--}65\%)$

$\text{Cardiac Output (CO)} = \text{SV} \times \text{Heart Rate (HR)}$

Shifts in Hemodynamic Parameters

• Increased Preload (e.g., rapid IV crystalloid infusion): Shifts Point B to the right (higher EDV). Stroke volume increases, widening the loop along the horizontal axis, with no immediate change in ESV or the ESPVR slope.
• Increased Afterload (e.g., acute severe arterial hypertension, aortic stenosis): Ventricle ejects against higher pressure. Point C moves upward; peak systolic pressure increases. Ejection ends sooner, shifting Point D rightward (increased ESV). Stroke volume decreases; the loop becomes taller and narrower.
• Increased Inotropy (e.g., dobutamine infusion, exercise): Enhances myocardial contractility, shifting the ESPVR line to the left (steeper slope). Point D moves to the left (decreased ESV). Stroke volume and ejection fraction increase markedly.

The Frank-Starling Law of the Heart

The Frank-Starling mechanism states that the force of ventricular contraction is directly proportional to initial muscle fiber length (end-diastolic volume). Stretching ventricular myocytes toward an optimal sarcomere length of $\sim 2.2\ \mu\text{m}$ increases the sensitivity of Troponin C to calcium and optimizes cross-bridge overlap. This intrinsic autoregulatory mechanism ensures that cardiac output from the right and left ventricles remains precisely balanced beat-to-beat.