3.4 Cardiac Cycle, Electrophysiology, and Ventricular Function

3.4 Cardiac Cycle, Electrophysiology, and Ventricular Function

A comprehensive understanding of cardiac mechanical phases, pressure-volume loops, electrophysiological ion channels, and coronary perfusion mechanics is essential for managing acute hemodynamic instability, administering inotropes and vasopressors, and protecting the myocardium during anaesthesia.

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1. Phases of the Cardiac Cycle and Pressure-Volume Loops

The cardiac cycle alternates between ventricular systole (contraction and ejection) and diastole (relaxation and filling), orchestrated by synchronized electrical activation.

  VENTRICULAR SYSTOLE                        VENTRICULAR DIASTOLE
  +---------------------------------------+  +---------------------------------------+
  | 1. Isovolumetric Contraction (S1)    |  | 4. Isovolumetric Relaxation (S2)     |
  |    - All valves closed; dP/dt max    |  |    - All valves closed; dP/dt drops   |
  | 2. Rapid Ventricular Ejection        |  | 5. Rapid Ventricular Filling (S3)    |
  |    - Aortic/Pulmonic valves open     |  |    - AV valves open; ~70% filling     |
  | 3. Reduced Ventricular Ejection      |  | 6. Diastasis (Reduced Filling)        |
  |    - Outflow slows; repolarization   |  | 7. Atrial Systole ('Atrial Kick', S4)|
  +---------------------------------------+  +---------------------------------------+

The Seven Mechanical Phases

1. Isovolumetric Contraction: Ventricular depolarization triggers contraction. Ventricular pressure exceeds atrial pressure, abruptly closing the atrioventricular (mitral and tricuspid) valves (First Heart Sound, S1). All four valves remain closed; intraventricular volume is unchanged while pressure escalates rapidly ($dP/dt_{\text{max}}$).
2. Rapid Ejection: Ventricular pressure surpasses aortic ($80\text{ mmHg}$) and pulmonary arterial ($10\text{ mmHg}$) diastolic pressures, forcing the aortic and pulmonic valves open. Approximately two-thirds of the stroke volume is rapidly propelled into the great vessels.
3. Reduced Ejection: Ventricular repolarization begins (T wave on ECG). The rate of ventricular pressure generation declines below aortic pressure, but forward blood flow continues briefly due to momentum. Intraventricular and aortic pressures peak and then decline.
4. Isovolumetric Relaxation: Ventricular pressure drops below great vessel pressures; backflow catches the valve leaflets, snapping the aortic and pulmonic valves shut (Second Heart Sound, S2). All valves remain closed; volume is constant while ventricular pressure falls precipitously.
5. Rapid Ventricular Filling: Ventricular pressure plummets below atrial pressure, forcing the mitral and tricuspid valves open. Rapid early ventricular filling accounts for $70-80\%$ of total end-diastolic volume. In patients with severe volume overload or poor chamber compliance, rapid deceleration of flow produces a pathological Third Heart Sound (S3).
6. Diastasis (Reduced Filling): Ventricular and atrial pressures near equilibrium; passive blood flow from the systemic and pulmonary veins into the ventricles slows to a trickle.
7. Atrial Systole ("Atrial Kick"): P wave on ECG triggers active atrial contraction, contributing the remaining $20-30\%$ of normal ventricular End-Diastolic Volume ($EDV$). In patients with non-compliant, hypertrophic ventricles (e.g. aortic stenosis, chronic hypertension), the atrial kick can contribute up to $40\%$ of stroke volume; forceful atrial contraction against a stiff ventricular wall produces a Fourth Heart Sound (S4). In these patients, the onset of atrial fibrillation produces acute hemodynamic collapse and pulmonary edema.

Jugular Venous Pulse (JVP) Tracing

  Pressure
     ^
     |   /\ a-wave (Atrial contraction)
     |  /  \   /\ c-wave (Tricuspid valve bulge in isovolumetric contraction)
     | /    \ /  \
     |/      x    \____________________/\ v-wave (Venous filling against closed tricuspid)
     |       descent                   \  \
     |       (Atrial relaxation)        \  \ y-descent (Tricuspid opens & empties)
     +--------------------------------------------------------> Time

• a wave: Atrial contraction (absent in atrial fibrillation; prominent cannon 'a' waves in complete heart block or junctional rhythm).
• c wave: Bulging of the tricuspid valve into the right atrium during RV isovolumetric contraction.
• x descent: Downward displacement of the tricuspid valve and annulus by ventricular shortening during ejection, combined with atrial relaxation.
• v wave: Passive venous filling of the right atrium against the closed tricuspid valve during ventricular systole (tall 'v' waves in tricuspid regurgitation).
• y descent: Rapid emptying of the right atrium into the right ventricle following tricuspid valve opening.

Ventricular Pressure-Volume Loops

  LV Pressure (mmHg)
  120 ^                 [ESPVR] Slope = Ees (Inotropy)
      |                   /------------------- [Aortic Valve Closes: ESV]
      |                  /|                  |
   80 | [Aortic Opens] -/-+                  |
      |                /  |                  |
      |               /   |   STROKE VOLUME  |
      |              /    |    (EDV - ESV)   |
      |             /     |                  |
      |            /      |                  |
    0 +-----------/-------+------------------+---- [EDPVR] (Diastolic compliance)
                         ESV                EDV
                          (Mitral Opens)    (Mitral Closes)
                          ---------------------> LV Volume (mL)

• Stroke Volume ($SV$): Width of the loop: $SV = EDV - ESV$.
• Stroke Work: The area enclosed by the loop represents external mechanical work performed during each cardiac contraction.
• End-Systolic Pressure-Volume Relationship (ESPVR): The upper-left boundary of the loop. Its slope, termed End-Systolic Elastance ($E_{\text{es}}$), is an intrinsic, load-independent index of myocardial contractility. Positive inotropic agents (epinephrine, calcium, milrinone) steepen $E_{\text{es}}$ and shift it leftward; negative inotropes (volatile anaesthetics, beta-blockers) flatten $E_{\text{es}}$ and shift it rightward.
• End-Diastolic Pressure-Volume Relationship (EDPVR): The curvilinear lower boundary reflecting passive ventricular compliance during diastole ($E = \Delta P / \Delta V$). Hypertrophy, ischemia, or pericardial constraint shift the EDPVR upward, meaning higher intracavitary pressures are required to achieve the same filling volume.
• Arterial Elastance ($E_a$): A measure of total afterload: $E_a \approx \frac{\text{End-Systolic Pressure}}{SV}$. Optimal ventriculo-arterial coupling occurs when $E_a / E_{\text{es}} \approx 0.6-1.0$.

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2. Determinants of Cardiac Output and Ventricular Interdependence

Cardiac output is governed by heart rate and stroke volume ($CO = HR \times SV$). Stroke volume is regulated by four interdependent physiological parameters:

1. Preload

Preload is the myocardial sarcomere length at the onset of contraction, clinically indexed by End-Diastolic Volume ($EDV$) or End-Diastolic Wall Stress.

• Frank-Starling Law: Within physiological limits, increasing end-diastolic volume stretches cardiac sarcomeres toward an optimal overlap length ($\approx 2.2\,\mu\text{m}$). This stretch enhances troponin C affinity for calcium, increases cross-bridge formation, and augments stroke volume.

2. Afterload

Afterload is the wall stress or tension the ventricle must overcome during systolic ejection.

• Law of Laplace for a Sphere: $\sigma = \frac{P \cdot r}{2h}$ Where $\sigma$ is myocardial wall stress, $P$ is transmural ventricular pressure, $r$ is internal chamber radius, and $h$ is myocardial wall thickness.
• Adaptive Remodeling: In chronic hypertension or aortic stenosis (pressure overload), the ventricle adds sarcomeres in parallel, producing concentric hypertrophy ($h$ increases). This normalizes systolic wall stress $\sigma$. In chronic mitral or aortic regurgitation (volume overload), sarcomeres are added in series, producing eccentric hypertrophy ($r$ dilates).

3. Contractility (Inotropy)

Contractility is the intrinsic velocity and force of myocardial fiber shortening at any given preload and afterload. It is determined by the amplitude of the intracellular calcium transient (calcium-induced calcium release via ryanodine receptors) and myofilament calcium sensitivity.

4. Heart Rate

Cardiac output increases linearly with heart rate up to an optimal physiological frequency ($\approx 140-160\text{ bpm}$). Extreme tachycardia severely shortens diastole (which comprises two-thirds of the cardiac cycle at $60\text{ bpm}$ but falls to $<40\%$ at $160\text{ bpm}$), drastically limiting ventricular filling ($EDV$ falls), reducing stroke volume, and precipitating hypotension.

Ventricular Interdependence and Pericardial Constraint

The right and left ventricles share a common muscular interventricular septum and are encased within a rigid, fibrous pericardial sac of fixed volume. Consequently, the volume or geometry of one ventricle directly influences the compliance and filling of the other:

• Acute RV Overload (Reverse Bernheim Effect): In acute pulmonary embolism, severe pulmonary hypertension, or RV infarction, acute RV volume expansion causes the interventricular septum to shift and bulge into the left ventricular lumen. This distorts LV geometry, markedly reduces LV compliance, impairs LV filling, and precipitates severe systemic hypotension.
• Pulsus Paradoxus: During spontaneous inspiration, negative intrathoracic pressure augments RV venous return; the expanding RV shifts the septum leftward, encroaching on the LV. In cardiac tamponade or severe status asthmaticus, this septal shift produces an exaggerated inspiratory drop in systemic systolic arterial pressure ($>10\text{ mmHg}$). Under positive pressure ventilation, the hemodynamic phase reverses (reversed pulsus paradoxus).

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3. Cardiac Electrophysiology: Fast vs Slow Action Potentials

  FAST-RESPONSE (Ventricular Myocyte)         SLOW-RESPONSE (SA / AV Nodal Cell)
  Membrane Potential (mV)                     Membrane Potential (mV)
  +30 ^     Phase 1 (Ito)                     +10 ^
      |    /\                                     |          Phase 0 (ICa-L)
    0 |   /  \______ Phase 2 (ICa-L, IKs)       0 |         / \
      |  /          \                             |        /   \ Phase 3 (IK)
      | / Phase 0    \ Phase 3 (IKr, IKs)     -40 |-------/-----+---
  -70 |/ (INa)        \                           |      /      |
  -90 +----------------\------ Phase 4 (IK1)  -60 +-----/-------+--- Phase 4 (If, ICa-T)

Fast-Response Action Potential (Atrial, Ventricular, and Purkinje Myocytes)

1. Phase 0 (Rapid Depolarization): Depolarization to threshold ($\approx -70\text{ mV}$) triggers opening of voltage-gated fast sodium channels ($I_{\text{Na}}$). Huge inward $\text{Na}^+$ current drives the membrane potential to $+20\text{ to }+30\text{ mV}$. Characterized by rapid upstroke velocity ($dV/dt_{\text{max}} \approx 200-400\text{ V/s}$).
2. Phase 1 (Early Partial Repolarization): Fast $\text{Na}^+$ channels inactivate rapidly; voltage-gated transient outward potassium channels ($I_{\text{to}}$) open briefly, moving $\text{K}^+$ outward.
3. Phase 2 (Plateau Phase): Prolonged electrical plateau ($\approx 200-300\text{ ms}$). Maintained by an exact equilibrium between inward calcium influx through voltage-gated L-type calcium channels ($I_{\text{Ca-L}}$) and outward potassium efflux through delayed rectifier potassium channels ($I_{\text{Kr}}$ and $I_{\text{Ks}}$). Calcium entering via $I_{\text{Ca-L}}$ triggers massive calcium release from the sarcoplasmic reticulum via ryanodine receptor type 2 (RyR2; calcium-induced calcium release).
4. Phase 3 (Rapid Repolarization): $I_{\text{Ca-L}}$ channels inactivate, while delayed rectifier potassium channels ($I_{\text{Kr}}$ and $I_{\text{Ks}}$) fully activate, producing rapid $\text{K}^+$ efflux that restores negative intracellular potential.
5. Phase 4 (Resting Membrane Potential): Stable resting potential at $\approx -90\text{ mV}$, maintained by high resting potassium conductance through inward rectifier potassium channels ($I_{\text{K1}}$) and the electrogenic $\text{Na}^+/\text{K}^+$ ATPase pump ($3\text{ Na}^+$ out for $2\text{ K}^+$ in).

Slow-Response Action Potential (SA Node and AV Node Pacemaker Cells)

Pacemaker tissue exhibits intrinsic rhythmicity (automaticity) and lacks fast sodium channels ($I_{\text{Na}}$ absent) and $I_{\text{K1}}$ channels. Maximum diastolic potential is unstable, beginning at $\approx -60\text{ mV}$.

1. Phase 4 (Spontaneous Diastolic Depolarization): Characterized by slow progressive depolarization toward threshold ($\approx -40\text{ mV}$):
   • Funny Current ($I_f$): Mediated by Hyperpolarization-activated Cyclic Nucleotide-gated (HCN4) channels. Activated by hyperpolarization at the end of repolarization; conducts a slow, inward mixed $\text{Na}^+/\text{K}^+$ current.
   • T-type Calcium Channels ($I_{\text{Ca-T}}$): Transient inward calcium current opening at negative potentials (around $-50\text{ mV}$), accelerating the final approach to threshold.
2. Phase 0 (Upstroke): Once threshold ($\approx -40\text{ mV}$) is reached, voltage-gated L-type calcium channels ($I_{\text{Ca-L}}$) open slowly. Depolarization is mediated entirely by calcium influx; upstroke velocity is slow ($dV/dt \approx 2-10\text{ V/s}$), accounting for normal AV nodal conduction delay.
3. Phases 1 and 2: Absent.
4. Phase 3 (Repolarization): Inactivation of $I_{\text{Ca-L}}$ and activation of delayed rectifier potassium channels ($I_{\text{K}}$) restores the membrane to its maximum diastolic potential ($-60\text{ mV}$).

Autonomic Control of Pacemaker Activity

• Sympathetic Stimulation: Noradrenaline binds $\beta_1$ adrenergic receptors $\rightarrow G_s$ protein coupling $\rightarrow$ adenylyl cyclase activation $\rightarrow \uparrow$ cAMP. Elevated cAMP directly binds HCN channels, increasing $I_f$ channel open probability. PKA phosphorylates L-type calcium channels ($I_{\text{Ca-L}}$), steepening the Phase 4 slope and accelerating conduction velocity (positive chronotropy and dromotropy). In working myocytes, PKA phosphorylates phospholamban, disinhibiting SERCA2a and speeding relaxation (positive lusitropy).
• Parasympathetic Stimulation: Acetylcholine released from the vagus nerve binds $M_2$ muscarinic receptors $\rightarrow G_i$ protein coupling $\rightarrow \downarrow$ cAMP (reducing $I_f$). Crucially, the $G_{\beta\gamma}$ subunit directly activates acetylcholine-activated potassium channels ($I_{\text{K-ACh}}$), causing hyperpolarization of the nodal membrane and flattening the Phase 4 slope (negative chronotropy and dromotropy).

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4. Coronary Blood Flow and Myocardial Oxygen Balance

Coronary Anatomy and Territorial Dominance

• Left Main Coronary Artery: Originates from the left aortic sinus of Valsalva; bifurcates into the Left Anterior Descending (LAD) and Left Circumflex (LCx) arteries. Supplies the anterior and lateral LV walls, apex, and the anterior two-thirds of the interventricular septum.
• Right Coronary Artery (RCA): Originates from the right aortic sinus of Valsalva. Supplies the RV free wall, inferior LV wall, and posterior third of the septum. Supplies the SA nodal artery in $\approx 60\%$ of patients and the AV nodal artery in $\approx 90\%$.
• Coronary Dominance: Defined by which vessel gives origin to the Posterior Descending Artery (PDA): $85-90\%$ are right-dominant (RCA gives off PDA); $10\%$ are left-dominant (LCx gives off PDA).

Phasic Coronary Perfusion Dynamics

Coronary perfusion is unique because the heart periodically compresses its own microvasculature:

1. Left Ventricle: During systole, high intramyocardial tissue pressures ($>120\text{ mmHg}$ in the subendocardium) collapse intramural capillaries and reverse subendocardial flow. Consequently, $\approx 80-85\%$ of left ventricular coronary blood flow occurs during diastole.
2. Right Ventricle: Peak systolic RV pressure is only $\approx 25\text{ mmHg}$, well below aortic systolic pressure. Therefore, right ventricular coronary perfusion is continuous across both systole and diastole.
3. Coronary Perfusion Pressure (CPP): $CPP = DBP - LVEDP$ Where $DBP$ is aortic diastolic blood pressure and $LVEDP$ is left ventricular end-diastolic pressure.

The Hemodynamic Trap of Tachycardia: Tachycardia impairs myocardial oxygen supply and demand simultaneously. First, it shortens diastolic filling time per minute (reducing oxygen supply via CPP). Second, it escalates myocardial oxygen consumption per minute ($MVO_2$, accelerating demand). In critical coronary stenosis, tachycardia precipitates acute subendocardial ischemia.

Myocardial Oxygen Balance ($MVO_2$)

Under resting conditions, myocardial oxygen consumption is exceptionally high: $8-10\text{ mL } \text{O}_2 / 100\text{g} / \text{min}$ (accounting for $\approx 10\%$ of total body oxygen consumption despite the heart weighing only $0.5\%$ of total body mass).

• High Basal Extraction: Myocardial tissue extracts $70-80\%$ of delivered oxygen at rest (coronary sinus saturation is only $\approx 30\%$, with a $P\text{O}_2$ of $18-20\text{ mmHg}$). Because extraction is already near maximal, any increase in myocardial metabolic demand must be met almost exclusively by an increase in coronary blood flow, mediated by metabolic vasodilation (adenosine, nitric oxide, $\text{K}^+$, acidosis).
• Determinants of $MVO_2$:
  1. Heart Rate: The single most important determinant of per-minute $MVO_2$.
  2. Ventricular Wall Tension / Stress: Governed by Laplace's Law (dependent on afterload/systolic pressure and cavity radius).
  3. Inotropic State (Contractility)
  4. Pressure Work vs Volume Work: Generating pressure against afterload consumes significantly more $\text{O}_2$ than ejecting volume against low impedance.
  5. Basal cellular metabolism and electrical activation: Accounts for $<20\%$ of total $MVO_2$.