Cardiac electrical activity Understanding the electrical activity of the heart is important because: The electrical activity precedes and induces the mechanical activity. The path, timing, and sequencing of the electrical activity is a large determinant of the effectiveness of the mechanical activity. Abnormalities in electrical activity are common causes of disability & death Measuring the electrical activity (ECG) aids in diagnosis of cardiac problems.

Electrical activity in biological systems is produced by diffusion of ions across membranes Ions diffuse across cell membranes through specific water-filled channels driven by the electric & concentration gradients across the membrane. In cardiac myocytes the resting membrane potential is produced mostly by diffusion of K+ down it’s concentration gradient out of the cell. Action potentials in nerve & muscle are due to rapid diffusion of Na+ into the cell down it’s electrochemical gradient. (Exception: action potentials in the SA and AV nodes are due to diffusion of Ca++ through L-type Ca++ channels.) Channels of interest in the cardiovascular system are: Voltage-gated: open with a change in membrane potential. Ligand gated: open in response to a hormone or intracellular signal. Stretch activated: open in response to stretch of a myocyte

The equilibrium potential for an ion is the membrane potential at which the effects of electrical and concentration gradients on diffusion of the ion balance each other. K+ = 4 mEq/L A- K+ = 135 mEq/L - + Electrical gradient: Negative resting membrane potential drives K+ into cell. Concentration gradient: Higher cell [K+] drives K+ out of cell. A - = intracellular anionic proteins & organic phosphates balance positive charge on K+. Equilibrium potential (or Nernst potential): If the membrane potential = the equilibrium potential for an ion, the rates of passive diffusion of the ion into and out of the cell are equal.

Equilibrium potential (Nernst potential) for Na+, K+ & Ca++ O/I = 14.5 Na+ 10 145 inside outside I/O = 33.75 K+ 135 4 inside outside O/I = 20,000 Ca++ 0.0001 2 inside outside Cardiac myocyte resting Membrane Potential = - 90 mV

Equilibrium potential compared to resting membrane potential (RMP) [inside]/[outside] Equilibrium potential, mV RMP, mV EK+ 135/4 - 94 - 90 Concentration & electrical forces are opposite; concentration > electrical ECl- 4/110 - 70 concentration & electrical forces are opposite; electrical > concentration ENa+ 10/145 + 70 Concentration & electrical forces act in same direction ECa++ .0001/2 + 132

Membrane pumps and potentials in a ventricular myocyte [Na+] = 10 mEq/L [K+] = 135 mEq/L Sarcoplasmic reticulum: Ca++ store Ca++ released during excitation Ca++ taken up during relaxation by Ca++ ATPase in SR (SERCA) Ca++ ATPase Ca++ [Na+] = 145 mEq/L [K+] = 4 mEq/L Voltage-gated L type Ca++ channel RMP = -90 mV Na+ Ca++ATPase 3 Na+ 2 K+ ATPase K+ passive active Na + Ca++ exchange

The resting membrane potential is primarily determined by diffusion of K+ [K+in] = 135 mEq/L Extracellular [K+], mEq/L Transmembrane potential, mV Resting membrane potential -150 -100 -50 5 10 20 30 50 1 2 3 Equilibrium potential for K+ Changing extracellular [K+] changes the concentration gradient for diffusion of K+ out of the cell and the equilibrium potential (EK+, Nernst potential) for K+. Parallel changes in EK and the resting membrane potential mean that diffusion of K+ is the main determinant of the resting membrane potential.

Changing extracellular [K+] changes the concentration gradient for diffusion of K+ out of the cell K+ = 4 mEq/L K+ = 135 mEq/L - + RMP = - 90 mV Normal Hyperkalemia: gradient for diffusion of K+ is decreased. K+ = 7 mEq/L K+ = 135 mEq/L - + RMP = - 75 mV K+ = 2 mEq/L K+ = 135 mEq/L - + RMP = - 95 mV Hypokalemia: gradient for diffusion of K+ is increased.

Effects of acute and chronic hyperkalemia Depolarization inactivates fast Na+ channels  excitability  cardiac conduction velocity Chronic Skeletal muscle weakness hyperkalemia depolarizes RMP RMP approaches threshold  excitability Acute “Symptoms of hyperkalemia … do not become manifest until the plasma potassium concentration exceeds 7.0 mEq/L , unless the rise in potassium concentration has been very rapid.” (B.D. Rose, UpToDate 2008).

Effects of acute and chronic hypokalemia Skeletal Muscle weakness Hypokalemia hyperpolarizes RMP RMP becomes more negative relative to threshold  excitability Acute Hyperpolarization activates some fast Na+ channels  excitability cardiac arrhythmias Chronic Symptoms usually occur only if plasma K+ is below 2.5 to 3 mEq/L

Phases of a ventricular myocyte action potential (0, 1, 2, 3, 4) ARP = absolute refractory period RRP = relative refractory period - 90 mV zero mV milliseconds 100 200 300 ARP RRP 2 3 4 1

Ion channels in the cardiac myocyte action potential Plateau: L Type Ca + + channels open, Some K+ channels close 40 mV: L-type Ca++ channel activation 1 2 zero mV 55 mV: fast Na+ channel inactivation Repolarization: Ca + + channels close, K+ channels open 3 70 mV upshoot: threshold for fast Na+ channel activation 4 gNa+ - 90 mV gCa++ gK+ g = conductance = 1/resistance

Summary of ionic currents in cardiac myocyte action potential 3 4 1 2 Phase Ionic current Upshoot Influx of Na+ 1 Transient repolarization Transient efflux of K+ 2 Plateau Influx of Ca++; decreased efflux of K+ 3 Repolarization Decreased influx of Ca++; increased efflux of K+ 4 Rest Resting potential set by efflux of K+ Influx: flow into cell. Efflux: flow out of cell

The upshoot of the AP is determined by diffusion of Na+ into the cell -100 -80 -60 -40 -20 20 40 Extracellular [Na+] Potential, mV Resting membrane potential Upshoot of action potential 15 30 50 150 Ventricular myocyte action potential As ECF [Na+] decreases (x axis) the magnitude (height) of the upshoot decreases (y axis) because the Na+ concentration gradient across the cell membrane decreases.

All or none law and force of contraction Skeletal Muscle Cardiac Muscle Action potential obeys “all or none” rule Single APs consistently release the same amount of Ca++ from the SR The amount of Ca++ released from the SR depends on the level of adrenergic stimulation. Increased force of contraction occurs by tetany or by recruitment of more motor units Increased force of contraction occurs by adrenergic stimulation resulting in more Ca++ interacting with the contractile mechanism Extracellular Ca++ is not needed for contraction Extracellular Ca++ is necessary for contraction (Ca++-Induced Ca++ Release) SR = sarcoplasmic reticulum

Pacemaker cells in the sino-atrial node set the normal heart rate The pacemaker potential is a spontaneously depolarizing membrane potential carried by a ”funny” Na+ current, If. This current is called “funny” because the responsible channels open as the cell membrane repolarizes (becomes more negative) past –50 mV. Other Na+ channels open when the membrane depolarizes. The upshoot of the action potential is a calcium current, ICa++. due to opening of L-type Ca++ channels. Repolarization is due to an outward K+ current, IK+ due to opening of K+ channels. -20 -60 -40 -80 Threshold – 55 mV outward inward ICa++ IK+ If Ionic currents

Path of excitation in the heart Sino-atrial node originates action potentials Atrial myocytes Atrioventricular node Bundle of His Right & left bundle branches Ventricular myocytes Purkinje fibers The heart is a syncytium. Depolarization (inward Na+ current) spreads from conducting tissue to myocytes & between myocytes via gap junctions. Gap junctions are located at the ends of myocytes and conduct current longitudinally. The velocity of conduction of APs is greatest in the Purkinje fibers. The AV node is the only pathway for conduction between atria & ventricles Conduction is delayed in the AV node allowing optimal ventricular filling during atrial contraction.

Conduction velocity Velocity of conduction of action potentials in cardiac myocytes and Purkinje fibers is directly proportional to: 1) Fiber diameter (greatest in Purkinje fibers). 2)The magnitude of the upshoot of the AP. 3) Rate of rise of the AP in phase 0 (increase slope of phase 0).  Magnitude of AP  Rate of rise of AP  Local current (depolarization)  Conduction velocity Both an increase in the magnitude of the action potential and a more rapid rate of rise of the AP in phase 0 cause greater depolarization of the cell membrane locally, opening more fast Na+ channels and increasing conduction,.

Conduction velocity, plasma [K+] & ischemia  Activity of Na+. K+ ATPase  Leak of K+ from cells  extracellular [K+] Gradual depolarization Inactivation of some Na+ channels  Local currents  Conduction velocity  K+ concentration gradient.  Magnitude of AP  Rate of rise of AP  potential driving Na+ entry Conduction velocity, plasma [K+] & ischemia Depolarization from any cause decreases conduction velocity in Purkinje fibers & myocytes.  Conduction velocity in hyperkalemia leads to abnormal conduction & disturbances in cardiac rhythm.

Automaticity & latent pacemakers In addition to the SA node, the AV node & Purkinje fibers may show pacemaker potentials. The heart rate is set by the pacemaker that is depolarizing at the fastest rate, normally the SA node. Damage or blockade of the SA node will allow slower pacemakers to take over & results in bradycardia (decreased HR). Pacemaker Intrinsic rate SA node 60- 100 B/min AV node & bundle of His 50- 60 B/min Purkinje fibers 30 – 40 B/min