physiology

1. MB., ChB., PhD., FCCP., FRS., FIBA
Professor of Physiology & Medicine

2. ORIGIN OF THE HEARTBEAT
INTRODUCTION
 The parts of the heart normally beat in orderly
sequence:
 Contraction of the atria (atrial systole) is followed by
contraction of the ventricles (ventricular systole)
 And during diastole all four chambers are relaxed
 The heartbeat originates in a specialized cardiac
conduction system and spreads via this system to all
parts of the myocardium

3. ORIGIN OF THE HEARTBEAT
 The structures that make up the conduction system
are the sinoatrial node (SA node), the internodal
atrial pathways, the atrioventricular node, the
bundle of His with its right and left branches, and the
Purkinje system
 The various parts of the conduction system and, under
abnormal conditions, part of the myocardium, are
capable of spontaneous discharge
 However, the SA node normally discharges most
rapidly, with depolarization spreading from it to the
other regions before they discharge spontaneously

4. ORIGIN OF THE HEARTBEAT
 The SA node is therefore the normal pacemaker, with
its rate of discharge determining the rate at which the
heart beats
 Impulses generated in the SA node pass through the
atrial pathways to the AV node, through this node to
the bundle of His, and through the branches of the
bundle of His via the Purkinje system to the
ventricular muscle
 The transmission velocity in the SA node is about 0.05
m/s, and in atrial muscle, bundle of His, and
ventricular muscle about 0.8 to 1 m/s

5. ORIGIN OF THE HEARTBEAT
 The conduction velocity in the AV node is about 0.03
to 0.05 m/s; however, in the Purkinje system it is about
4 m/s, i.e., 100 times greater than in the nodal systems
 Each of the cell types in the heart contains a unique
electrical discharge pattern; the sum of these electrical
discharges can be recorded as the electrocardiogram
(ECG)
 The ECG is clinical useful in aiding diagnosis of heart
diseases such as arrhythmias, and acute myocardial
infarction, and in monitoring critically ill patients in
coronary care units (CCU/ICU)

6. ORIGIN AND SPREAD OF CARDIAC
EXCITATION
ANATOMICAL CONSIDERATIONS
 In the human heart, the SA node is located at the
junction of the superior vena cava with the right
atrium
 The AV node is located in the right posterior portion
of the interatrial septum
 There are three bundles of atrial fibres that contain
Purkinje-type fibres and connect the SA node to the
AV node, these are:
 The anterior, middle (tract of Wenckebach), and
posterior (tract of Thorel)

7. ORIGIN AND SPREAD OF CARDIAC
EXCITATION
 Bachmann’s bundle is sometimes used to identify a
branch of the anterior tract that connects the right and
left atria
 Conduction also occurs through atrial myocytes, but it
is more rapid in these bundles
 The AV node is continuous with the bundle of His,
which gives off a left bundle at the top of the
interventricular septum and continues as the right
bundle branch

8. ORIGIN AND SPREAD OF CARDIAC
EXCITATION
 The left bundle branch divides into an anterior fascicle
and a posterior fascicle
 The branches and fascicles run subendocardially down
either side of the septum and come into contact with
the Purkinje system
 From the Purkinje system fibres spread to all parts of
the ventricular myocardium

9. HISTOLOGY OF THE CONDUCTION SYSTEM
 The histology of a typical cardiac muscle cell (e.g., a
ventricular myocyte) is described in Chapter 5
 The conduction system is composed of, for the most
part, of modifies cardiac muscle that has fewer
striation and indistinct boundaries
 Individual cells within regions of the heart have
unique histological features
 Purkinje fibres, specialized conduction cells, are large
with fewer mitochondria and striation and distinctly
different from a myocyte specialized for contraction

10. HISTOLOGY OF THE CONDUCTION SYSTEM
 Cells within the SA node and, a lesser extent the AV
node are smaller and sparsely striated, but unlike
Purkinje fibres are less conductive due to their higher
internal resistance
 The atrial muscle fibres are separated from those of
the ventricles by a fibrous tissue ring
 And normally, the only conducting tissue between the
atria and ventricles is bundle of His

11. INNERVATION OF THE CONDUCTION
SYSTEM
 The SA node develop from structure on the right side
of the embryo and the AV node from structures on the
left
 That is why in the adult the right vagus is distributed
mainly to the SA node and the left vagus to the AV
node
 Similarly, the sympathetic innervation on the right
side is distributed primarily to the SA node, and the
sympathetic innervation on the left side primarily to
the AV node

12. INNERVATION OF THE CONDUCTION
SYSTEM
 On each side, most sympathetic fibres come from the
stellate ganglion
 Noradrenergic fibres are epicardial, whereas the vagal
fibres are endocardial
 However, connections exist for reciprocal inhibitory
effects of the sympathetic and parasympathetic
innervations of the heart on each side

13. INNERVATION OF THE CONDUCTION
SYSTEM
 Thus acetylcholine acts presynaptically to reduce
noradrenaline release from sympathetic nerves
 Conversely, neuropeptide Y released from
noradrenergic endings may inhibit the release of
acetylcholine

14. PROPERTIES OF CARDIAC MUSCLE
 The electrical responses of cardiac muscle and nodal
tissue and the ion fluxes that underline them are
discussed in detail in Chapter 5
 Myocardial fibres have a resting membrane potential
of approximately -90 mV
 The individual fibres are separated by membranes, but
depolarization spreads radially through them as if they
were a syncytium because of the presence of gap
junctions

15. PROPERTIES OF CARDIAC MUSCLE
 The transmembrane action potential of a single
cardiac muscle is characterized by rapid
depolarization (phase 0)
 An initial rapid repolarization (phase 1), a plateau
(phase 2)
 And a slow repolarization (phase 3) that allows return
to the resting membrane potential (phase 4)
 The initial depolarization is due to Na influx through
rapid opening of Na channels (the Na current, INa)

16. PROPERTIES OF CARDIAC MUSCLE
 The inactivation of Na channels contributes to rapid
repolarization phase (phase 1)
 Ca influx through more slowly opening Ca channels
(the Ca current, ICa) produces the plateau phase
(phase 2)
 Repolarization is due to net K efflux through the
multiple types of K channels
 Recorded extracellularly, the summed electrical
activity of all cardiac muscle fibres is the ECG

17. ELECTROCARDIOGRAM
 The timing of the discharge of individual unit in
relative to the ECG is shown in Figure 29-1
 The ECG sums the discharges from the SA node, atrial
muscle, AV node, common bundle, bundle branches,
Purkinje fibres, and ventricular muscle
 Note that the ECG is a combined electrical record and
thus the overall shape reflects electrical activity from
each different regions of the heart indicated above

18. PACEMAKER POTENTIAL
 Rhythmically discharging cells have a membrane
potential that, after each impulse, declines to the
firing level
 Thus, this prepotential or pacemaker potential
triggers the next impulse
 At the peak of each impulse, IK begins and brings
about repolarization, IK then declines, and a channel
permeable to both Na and K is activated

19. PACEMAKER POTENTIAL
 Because this channel is activated following
hyperpolarization, it is referred to as an “h” channel
 However, because of its unusual (funny) activation it
has also been dubbed an “f” channel and the current
produced as “funny current”
 As Ih increases, the membrane begins to depolarize,
forming part of the prepotential, Ca channels then
open

20. PACEMAKER POTENTIAL
Ca channels
 There are of two types of Ca channels in the heart, the
T (for transient) and the L (for long-lasting)
 The calcium current (ICa) due to opening of the T
channels complete the prepotential
 And ICa due to opening of L channels produce the
impulse
 Other channels are also involved, and there is evidence
that local Ca release from the endoplasmic reticulum
(Ca sparks) occurs during the prepotential

21. PACEMAKER POTENTIAL
 The action potential in the SA and AV nodes are
largely due to Ca, with no contribution by Na influx
 Consequently, there is no sharp, rapid depolarizing
spike before the plateau, as there is in other parts of
the conduction system, and in the atrial and
ventricular fibres
 In addition, prepotentials are normally prominent only
in the SA and AV nodes

22. PACEMAKER POTENTIAL
 However, “latent pacemaker” are present in other
portions of the conduction system that can take over
when the SA and AV nodes are depressed or
conduction from them is blocked
 Atrial and ventricular muscle fibres do not have
prepotentials, and they discharge spontaneously only
when injured, eg, in myocardial ischaemia or when
they are abnormal

23. PACEMAKER POTENTIAL
 When cholinergic vagal fibres to nodal tissue are
stimulated, the membrane becomes hyperpolarized
and the slope of the prepotential is decreased
 This is because the acetylcholine released at the nerve
endings increases the K conductance of nodal tissue
 This action is mediated by M2 muscarinic receptors,
which, via the βγ subunit of the G protein, open a
special set of K channels

24. PACEMAKER POTENTIAL
 The resulting IKAch slows the depolarizing effect of Ih
 In addition, activation of the M2 receptors decreases
cyclic adenosine 3,5’-monophosphate (cAMP) in cells,
and this slows the opening of Ca channels
 The result is a decrease in firing rate and a decrease in
the heart rate (bradycardia)
 Strong vagal stimulation may abolish spontaneous
discharge for sometime

25. PACEMAKER POTENTIAL
 Conversely, stimulation of the sympathetic cardiac
nerves speeds the depolarizing effect of Ih, and the rate
of spontaneous discharge increases
 Noradrenaline secreted by the sympathetic endings
binds to β1 receptors, and the resulting increase in
intracellular cAMP facilitates the opening of the L
channels, increasing ICa and the rapidity of the
deporalization phase of the impulse
 This leads to increase in the heart rate or tachycardia

26. PACEMAKER POTENTIAL
 The rate of discharge of the SA node and other nodal
tissue is influenced by temperature and by drugs
 The discharge frequency is increased when the
temperature rises, and this may contribute to the
tachycardia associated with fever
 Digitalis depresses nodal tissue and exerts an effect
like that of vagal stimulation, particularly on the AV
node

27. DIGITALIS
 The term digitalis is used to designate the entire class of
cardiac glycosides
 The most commonly used cardiac glycoside is digoxin
 Digoxin is about 70 per cent absorbed when given in tablet
form but it is almost completely absorbed when given as an
encapsulated liquid concentrate (lanoxicaps)
 By its inotropic effect, digitalis improves the circulation in
patients with heart failure
 Digitalis also has a parasympathetic effect and causes a
diminution of the sympathetic effect on the heart
 Finally, it has a direct vasoconstrictive action

28. DIGITALIS
 Toxicity occurring during chronic administration is
common, although acute poisoning is infrequent
 These include nausea, vomiting, dizziness, anorexia,
fatigue and drowsiness
 Rarely, confusion, visual disturbances and
hallucinations occur
 In general, the therapeutic serum concentration of
digoxin in adults is 1.0 to 2.0 ng/ml
 Serum levels of digoxin are helpful in confirming
clinical suspicion of digitalis toxicity, especially if the
serum digoxin level is greater than 3.0 ng/ml

29. DIGITALIS
 Digitalis-induced arrhythmias may be due to the
drug’s parasympathetic effects on the heart and the
effects related to enhanced ectopy
 Signs of increased vagal effects include sinus
bradycardia, SA exit block, and AV nodal block,
usually of Wenckebach type
 Examples of digitalis-induced ectopy include
premature atrial contraction, junctional tachycardia,
and ventricular ectopy activity
 Death, if it occurs, may be due to ventricular
tachycardia and/or ventricular fibrillation

30. DIGITALIS
 Treatment of digitalis toxicity depends on the
seriousness of the arrhythmia
 Activated charcoal is commonly administered to
patients presenting within one hour of ingestion of an
acute overdose
 A 12 lead ECG is performed and cardiac monitoring
instituted
 Correction of hypokalaemia, together with cessation of
digitalis, may be all that is needed to control digitalis-
induced tachyarrhythmias

31. DIGITALIS
 Significant bradycardias may respond to atropine, although
temporary pacing is sometimes needed
 Anecdotal reports indicate that amiodarone, bretylium,
and intavenous magnesium can suppress life-threatening
arrhythmias due to digitalis intoxication
 If available, digoxin-specific antibody fragment should be
administered when there are severe ventricular
arrhythmias or unresponsive bradycardias
 The Fab fragments can rapidly reverse digoxin-induced
toxicity
 The glycoside is bound to the Fab fragments and
eliminated by the renal route

32. CLINICAL BOX 29-1
USE OF DIGITALIS
 Digitalis, or its clinically useful preparations (digoxin
and digitoxin) have been prescribed in medical
literature for more than 200 years
 It was originally derived from the foxglove plant
(digitalis purpurea is the name of the common
foxglove)
 Correct administration can strengthen contractions
through digitalis inhibitory effect on the Na K ATPase
 Resulting in greater amount of Ca release and
subsequent changes in contraction forces

33. CLINICAL BOX 29-1
USE OF DIGITALIS
 Digitalis can also have an electrical effect in decreasing
AV conduction velocity and thus altering AV
transmission to the ventricles
 It slows conduction and prolong the refractory period
in the AV node
 This effect helps control ventricular rate in atrial
fibrillation, and may interrupt supraventricular
tachycardias involving the AV node

34. THERAPEUTIC HIGHLIGHTS
 Digitalis preparations have been used for treatment of
systolic heart failure for 200 years
 It augments contractility, thereby improving cardiac
output, improving ventricular emptying, and
decreasing ventricular filling pressures
 Digoxin can also be used to provide rate control in
patients with heart failure and atrial fibrillation
 In patients with severe heart failure (NYHA class III-
IV), digoxin reduces likelihood of hospitalization for
heart failure, although it has no effect on long-term
survival

35. THERAPEUTIC HIGHLIGHTS
 Digitalis (digoxin) has also been used to treat
supraventricular arrhythmias such as atrial
fibrillation and atrial flutter
 In this scenario, digitalis reduces the number of
impulses transmitted through the AV node thus,
provide effective rate control
 In both these instances alternative treatments
developed over the past 20 years and the need to
tightly regulate dose due to the significant potential
for side effects have reduced the use of digitalis

36. THERAPEUTIC HIGHLIGHTS
 However, with better understanding of mechanism
and toxicity, digitalis and its clinically prepared
derivatives remain important drugs in modern
medicine

37. SPREAD OF CARDIAC EXCITATION
 Depolarization initiated in the SA node spreads
radially through the atria, then converge in the AV
node
 Atrial depolarization is complete in about 0.1 sec
 Because conduction in the AV node is slow, a delay of
about 0.1 sec (AV nodal delay) occurs before
excitation spreads to the ventricles
 It is interesting to note that when there is lack of
contribution of INa in the depolarization (phase 0) of
the action potential, a marked loss of conduction is
observed

38. SPREAD OF CARDIAC EXCITATION
 This delay is shortened by stimulation of the
sympathetic nerves to the heart, and lengthened by
stimulation of the vagi
 From the top of the septum, the wave of depolarization
spreads in the rapidly conducting Purkinje fibres to all
parts of the ventricle in 0.08-0.1 sec
 In humans, depolarization of the ventricular muscle
starts at the left side of the interventricular septum
 It moves first to the right across the mid portion of the
septum

39. SPREAD OF CARDIAC EXCITATION
 The wave of depolarization then spreads down the
septum to the apex of the heart
 It returns along the ventricular walls to the AV groove,
proceeding from the endocardial to the epicardial
surface
 The last part of the heart to be depolarized is the
posterobasal portion of the left ventricle, the
pulmonary conus, and uppermost portion of the
septum

40. TABLE 29-1
CONDUCTION SPEEDS IN CARDIAC TISSUE
Tissue Conduction rate (m/s)
 SA node 0.05 m/s
 Atrial pathway 1
 AV node 0.05
 Bundle of His 1
 Purkinje system 4
 Ventricular muscle 1