BENG 230C

Cardiovascular Physiology

Cardiac Impulse Conduction

Including slides courtesyProfessor Wayne GilesUniversity of Calgary

Levy and Pappano, Chapter 3Kléber AG, Rudy Y (2004)Basic mechanisms of cardiac impulse propagation and associated arrhythmias.Physiol Rev. Apr;84(2):431-88. Review.

Reading

Willem Einthoven (1860-1927)

1903: Invented ECG machine1924: Received Nobel Prize in Medicine

Sinus Node and the Purkinje Systemof the Heart

Adapted from figure 10-1, Guyton & Hall

Note:1) Myogenic spontaneous pacing2) Pattern of conduction3) Apex and base of

the ventricle1) Purkinje system2) Transmural conduction

Cardiac Conduction Sequence

Electrocardiogram (ECG)

Conduction of electrical impulses through the heartMeasures and records intensity (millivolts) and the time intervals involved

Conventional Arrangement of Electrodes for Recording Electrocardiogram

Adapted from figure 11-6, Guyton & Hall

Conventional Arrangement of Electrodes for Recording Electrocardiogram

Adapted from figure 11-6, Guyton & Hall

ECG Leads

12 Lead ECGV1-6 are precordial (chest) leads

The Important Deflections and Intervals of a Typical Scalar Electrocardiogram

Adapted from figure 22-33, Berne & Levy

Organization of Cardiac Muscle FibersThe Electrophysiological Syncytium

‘Intercellular Communication’

Adapted from figure 9-8, Sherwood

Cardiac Gap Junctions

Intercellular current flow in mammalian ventricle

Cable Equation for Continuous Propagation

Wavefront Propagating Towards a BoundaryCurrents reflected from boundary reduce electrical load on cells proximal to

the boundary

Effects of wavefront collision on the upstroke of the transmembrane action potential and the Na+ inward current. Top left: change of membrane potential (Vm) during action potential upstroke. Bottom left: maximal upstroke velocity of transmembrane action potential in V/s. Top right: Na+ inward current (INa). Bottom right: Na+ conductance (gNa). From Spach and Kootsey

Dispersion of local current at front of propagating wavecurrent-to-load mismatch reduces current density, locally slows AP upstroke

and reduces conduction velocity

Effect of wavefront dispersion on the upstroke of the transmembrane action potential and the Na+ inward current. A, inset: 2-dimensional strand of excitable tissue emerging into a large area.Action potential upstrokes (A) and dVm/dt traces (B) show two components that are most prominent at the site of tissue expansion (signals 6). C: time course of Na+ conductance, gNa. D: time course of Na+ inward current, INa. Note that INa increases at the expansion site (site 6). [from Fast and Kléber.]

Wavefront Curvature

Effect of curvature on propagation. Left: stimulation of a perfused rabbit ventricular epicardial layer with a single electrode (point stimulation from black dot) produces a convex excitation front. Right: stimulation with a line of electrodes (line stimulation) produces an almost flat excitation front. Numbers correspond to activation times in milliseconds. Isochrone lines are shown at intervals of 3 ms. Average longitudinal velocity of curved wave is 13% slower than that of flat wave. [from Knisley and Hill.]

Discontinuous PropagationPropagation velocity depends on the repartition into subelements of low and high resistance. At high discontinuity, conduction is only maintained within a certain range, characterized by a match between the value of the low resistance elements, the number N of elements, and the value of R which separates them

Left: discontinuity is defined by a row of excitable elements (Rlow) separated by resistors (Rhigh).Right: change of propagation velocity (θ) vs. effective or overall longitudinal resistance (Ri) plotted in the bottom panel is equal to the average longitudinal resistance. Case A: continuous case, θ2 α 1/Ri

Case B: moderate discontinuity, Rlow = 200Ω/cm, Rhigh = 5,000 Ω /cmCase C: marked discontinuity, Rlow = 200, Rhigh = 10,000 [Modified from Joyner]

Safety Factor in Structurally Nonhomogeneous TissueA–D: conduction along a fiber with inhomogeneous intercellular coupling.A: starting from the junction between cells 79 and 80, gap junction conductance (gj) is increased from 0.08 to 2.5 µS.B: action potentials (Vm)C: safety factor (SF) along fiber (line graph); local charge contributions from INa (QNa) and ICa(L) (QCa) are shown in bar graph. D: peak values of INa (INa,max; solid line) and ICa(L) [ICa(L),max; dashed line] along fiber.E–H: propagation across an expansion site.E: fiber expansion (branching) is introduced at cell 80 and repeated twice with an expansion ratio (ER) of 2.3F: action potentials; numbers indicate selected cells.G: line indicates SF along fiber; bars indicate QNa and QCa. H: INa,max(solid line) and ICa(L),max (dashed line) along fiber.[from Wang and Rudy].

Effects of Cell Size and Gap Junction Distribution

Effect of cell size and distribution pattern of gap junctions on cell-to-cell propagation delay (A) and upstroke velocity of the action potential (B) during transverse propagation. Column arepresents values simulated from a model of the normal adult dog heart cell with gap junctions located predominantly at the longitudinal ends. Column d represents values of the normal neonatal rat heart cell with uniformly spaced gap junctions around the cell perimeter. Column bcorresponds to a virtual cell with the cell size of a dog myocyte and the gap junction pattern of a neonatal rat heart cell; accordingly, column c corresponds to a virtual cell with the cell size of a neonatal rat myocyte and the gap junction pattern of an adult dog myocyte. Note that cell size has a significantly larger effect than gap junction pattern on both parameters. [from Spach et al.]

Effects of Reduce Gap Junctional Conductance

AP upstrokes from the edge elements of neighboring cells are shown in A and B (see inset).A: Normal gap junction conductance B: Reduced couplingFor normal coupling (A), intercellular conduction delay at the gap junction (shaded) is approximately equal to intracellular (myoplasmic) conduction time. A 10-fold decrease in gap junction conductance (B) increases the intercellular delay and decreases intracellular conduction time dramatically, resulting in gap junction dominance of macroscopic conduction velocity.[Modified from Shaw and Rudy]

Subcellular Heterogeneity of Activation

Subcellular heterogeneity of activation (A), dV/dtmax (B), and INa (C) in a network of simulated dog myocytes. Left graphs correspond to longitudinal propagation from left to right, and right graphs correspond to transverse propagation from top to bottom. Note the close direct correspondence between isochrone spacing and dV/dtmax and the inverse correspondence to INa during both transverse and longitudinal propagation. Immediately after passage of the wavefront through gap junctions, dV/dtmax and conduction velocity show low values and INa is high (sites of current dispersion) while the inverse situation is present before the passage of the waves through gap junctions (sites of partial collision).

Conscious rodent ECG recording device

Sliding headcone

Adjustable end gate

Sliding electrodeplate

IP injection opening

Select regions without highfrequency noise

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Criteria for data analyses must be fine-tuned for each application

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Lead 1 ECG

Respiration

Mouse Raw Data Traces

Analysis of means of ECG signal parameters

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"Pmax" 86

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"Qon" 194

"Qmax" 199

"Ron" 202

"R" 210

"S" 217

"J" 220.9216

"Tmax" 241

"Tend" 266

HR

P-wave

QRS

T-wave

A B

Voltage-Sensitive Dye Imaging of Mouse Ventricle

RV

LV

Mouse ventricular activation: Sinus

rhythm

Activation of Mouse Atria

Left atrium

Right atrium

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Apex

Pacing site

RV LV

Apex

Activation Pattern in Sinus Rhythm

Durrer et al, Circulation, 41:899-912, 1970

Rat Human

Motion Artifacts

Activation and Repolarizationin Acute Ischemia

• Coronary artery ligation ischemic area

• Recording conditions:– 2 mM Ca2+

– 3 μM Cytochalasin-D for motion artifact reduction

Ischemic zone

Ventricular Fibrillation