Electrophysiology

• The Cardiovascular system is an organ system consisting of;
• Pump (heart)
• Liquid (blood)
• Tubes (vessels)

Pump - Heart

• The heart is a hollow muscular organ that, through regular contractions, ensures the circulation of blood in the body.
• The wall of the heart chambers consists of 3 layers:
• Endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels.
• Myocardium is striated muscle in appearance but with some key differences to skeletal muscle
• Pericardium is a double-walled sac containing the heart and the roots of the great vessels; consists of two layers, a serous (visceral) layer and a fibrous (parietal) layer, which in turn encloses the pericardial cavity, which contains pericardial fluid.
• Valves consist of atrioventricular (mitral, tricuspid) + papillary muscles + chordae tendineae + semilunar (aortic, pulmonary)

Liquid - Blood

• Blood is a viscous fluid, consisting of the plasma and blood cells.
• It delivers necessary substances such as nutrients and oxygen to the cells.
• It transports metabolic waste products away from those same cells.
• The main functions of blood are:
• Transportation
• Protection
• Homeostasis, like osmotic pressure, pH, ions
• Temperature regulation

Tubes - Vessels

• The cardiovascular system includes blood vessels to transport blood;
• Arteries
• Arterioles
• Capillaries
• Venules
• Veins

General Features of The Heart

• It is a 4-chambered organ
• It is self-activated by intrinsic pacemaker activity
• Two separate pumps (RV, LV) are supplied with two secondary pumps (RA, LA)
• Atrial pumps contract prior to the contraction of ventricles
• Cardiac muscle contraction provides the driving force (pressure gradient) for the blood flow

The Five Cardiac Subsystems are:

• The electrical pacemaker and conducting system
• The heart muscle
• The valves of the heart
• The coronary circulation
• The autonomic innervation of the heart

Basic Features of The Heart Function

• Regular electrical activity of the heart originating in the pacemaker cells precedes mechanical activity (contraction)
• The sequence of electrical and mechanical events that repeats rhythmically is called the CARDIAC CYCLE.
• The cardiac cycle consists of contraction (SYSTOLE) and ventricular relaxation (DIASTOLE).
• During systole, blood is ejected from the heart chambers into the aorta and pulmonary artery.
• During diastole, the chambers are filled with blood returning through the venous system.
• Automaticity is the heart's pacemaker activity generating a periodical electrical oscillation
• Autonomy is the heart's independence of external regulation for initiation of contraction
• Rhythmicity refers to the action potential’s regular intervals; average heart rate of between 60 – 90 beats per minute.

Two Major Types of Action Potential in the Heart

• Working ventricular myocardial cell action potential features: RMP -80 mV AP elicited after external stimulation (from conduction system or neighbouring cardiomyocytes)
• Pacemaker cell of SA node action potential features:
• MDP -65 mV
• Self-excitable

Working Cardiomyocytes

• Resting Membrane Potential is -80 mV

• Working Cardiomyocytes present 5 phases;

• Phase 0 – upstroke – INa

• Phase 1 – brief initial repolarization K (ITO)

• Phase 2 – plateau phase (ICAL)

• Phase 3 – repolarization (IK)

• Phase 4 – resting membrane potential (IK1)

• Phase 0 consists of depolarization, or upstroke with Na (INa)

• Phase 1 consists of initial (transient) repolarization through K (Ito)

• Phase 2 is the plateau phase that flows through ICaL

• Phase 3 is the terminal repolarization which flows through IK

• Phase 4 is the resting membrane potential which flows through IK1

Resting Membrane Potential

• Resting membrane potential is around -80 mV, and is stable
• Resting membrane potential is close to Ek
• IK1, INabgr are both crucial background currents, at the value of RMP at which INa and Ik are equal (Ix = gx × driving potential)

AP - Phase 0 – Depolarization – Na – INa

• The threshold for depolarization is around -60 mV, with a high driving potential for Na
• The membrane potential goes up to +30 mV
• INa lasts 1-2 ms, and is a voltage-gated channel that has activation and inactivation gates
• Determines velocity of AP conduction
• Depolarization is a gating signal for neighbouring cardiomyocytes
• IK1 is blocked

AP - Phase 0 – Depolarization – Na – INa (continued)

• Activation occurs once at -60 mV, increasing Na permeability 1000x, and the MP approaches ENa
• Inactivation happens slower than activation, closing a majority of channels around 0 mV
• Recovery happens within the range of -60 to -80 mV

AP - Phase 1 – Initial Repolarization – K (Ito)

• Transient K+ current moves from the cell - Ito
• Voltage gated channel with 2 gates (A, I, R)
• Opens in the course of depolarization

AP - Phase 2 – Plateau – Ca (ICAL)

• This phase consists of slow repolarization, achieved through Ical – voltage gated channel with 2 gates (A, I, R)
• Higher density in sarcolemma of T-tubules
• Opens in the course of depolarization, cca -40 mV
• Inactivation governed by voltage IC and IC Ca2+ concentration
• Channel phosphorylation by cAMP-dependent protein kinase
• Long depolarization essential for refractoriness
• Replenishes IC Ca2+
• CICR
• Recovery starts at -40 mV

AP - Phase 3 – Terminal Repolarization (IK)

• Phase 3 contains also terminal rapid repolarization
• Ik – in reality 2 voltage gated channels with 1 gate (A, D) – Ikr and Iks rapid, slow
• Activation governed by voltage and IC Ca2+ concentration
• It increases after inactivation of Ca channels (delayed rectifier)
• 𝛽-adrenergic stimulation increases Iks
• Deactivation -60 mV
• In the range -60 to -80 mV IK₁ becomes major repolarizing current

Heterogeneity of AP of Working Cardiomyocytes

• Different duration of AP
• Shorter in RV, in outer layers of cardiomyocytes
• The cells activated first should still be refractory when depolarization reaches subepicardial cardiomyocytes
• During a longer plateau phase more Ca2+ enters the cell, so subsequent contraction is stronger

Major Channels in Working Cardiomyocytes

Channel | Gating | Functional Role

• ---------|----------|---------- Fast sodium current | V (-65 to -80 mV) | Phase 0; activation (-65 mV); inactivation; recovery (-60 to -80 mV) Calcium current | V (-40 mV) | Phase 2, activation cca -40 mV, 𝛽-adrenergic stimulation ↑ Transient outward current | V (0 mV) | Phase 1, activation cca 0 mV Delayed rectifier | V | Phase 3 Ligand-activated potassium currents | L | Membrane hyperpolarization (phase 4) Potassium background current | V | Phase 4, closes during phase 0, finishes repolarization

Sinoatrial Node

Pacemaker cells – pale, cca 5 µm

• Inflow tract of the RA, close crista terminalis and SCV

• Maximum diastolic potential (MDP) -60 mV

• Unstable RMP - spontaneous Slow Diastolic Depolarization (SDD) -IbgNa, -I (-60 mV), -Ісат (-60 mV), -ICAL (-35 mV), -Ik deactivated

• Missing IK1

• INa inactivated

• The fastest normal pacemaker maintains between 60-80/min

Sinoatrial Node Pacemaker Cell

• Phase 0 has a rapid depolarization through Ca (ICAL)
• Phase 3 has terminal repolarization through (Ikr,s)
• Phase 4 has slow diastolic depolarization (INabg, Cat, CaL, If)

SDD

• IbgNa • If - hyperpolarization-activated current (-60 mV), can be affected by adrenergic stimulation • Ісат (-60 mV) - transient • ICaL (-35 mV) - long-lasting • Ikr,s deactivated

Major Channels in Sinoatrial Pacemaker Cells

Channel | Gating | Functional Role

• ---------|----------|---------- Sodium background current | V | Phase 4 (SDD) Transient calcium current | V | Phase 4 (SDD), activation cca -60 mV Calcium current | V | End phase 4 + phase 0, activation cca -40 mV, 𝛽-adrenergic stimulation ↑ Hyperpolarization-activated current | V | Beginning phase 4 (SDD), „funny“ current Delayed rectifier | V | Phase 3, deactivates at -60 mV Ligand-gated potassium currents | L | HR regulation Fast sodium current | V | INACTIVATED! Potassium background current | V | ABSENT!

Conducting System

• Automaticity (spontaneous production of AP, self-excitation)
• Conduction of AP
• Synchronization of mechanical activity of the heart

Sequence of Excitation

• Generation:
• Sinoatrial node – right atrium (determines the heart rate)
• Conduction:
• Bachman's bundle and internodal pathways
• Atrioventricular node (base of RA, propagation of AP relatively slow)
• Bundle of His (interventricular septum)
• Right and left bundle branches
• Purkinje fibers

Sinoatrial Node (SA Node)

• Rate 60 – 80/min, sinus rhythm
• Slow conduction (0.05 m/s) – velocity of conduction is further decreased by hypoxia, low temperature

at the center of Koch's triangle

• at the septal leaflet of the tricuspid valve, the coronary sinus, and the membraneous part of the interatrial septum
• Slow conduction (0.02 m/s) – atrioventricular delay
• Frequency filter- max. 230/min
• Zones atrionodal (A-N), Nodal (N), Nodal-His (N-H)

Purkinje Fibres

• Conduction velocity up to 4 m/s • Longer AP • RMP higher (-90 mV), unstable, role of If • Idioventricular rhythm 15 – 30/min

Conduction Velocity (m/s)

• SA node has a velocity of 0.05 m/s
• Atrial pathways have a velocity of 1 m/s
• AV node has a velocity of 0.05 m/s
• Bundle of His has a velocity of 1 m/s
• Purkinje system has a velocity of 4 m/s
• Ventricular muscle has a velocity of 1 m/s

Determinants of Conduction Velocity

1. High density of gap junctions (nexus, tight junction) in the sarcolemma within cardiomyocyte connections

• Phosphorylation
• IC Ca2+ concentration

2. Value of RMP; affects the speed of depolarization
3. Cardiomyocyte diameter - length (space) constant