Mechanisms Of Arrhythmia
Arrhythmias are abnormalities
of the heart rate or rhythm caused by disorders of impulse generation or
conduction.
All parts of the cardiac conduction
system demonstrate a spontaneous phase 4 depolarization (automaticity),
and are therefore potential or latent pacemakers. Because sinoatrial
node (SAN) pacemaking is of the highest frequency (70–80 beats/min), it causes overdrive
suppression of pacemaking by the atrioventricular node (AVN) (50–60
beats/min) or Purkinje fibres (30–40 beats/min). However, ischaemia,
hypokalaemia, fibre stretch or local catecholamine release may increase
automaticity in latent pacemakers, which can then ‘escape’ from SAN dominance
to cause arrhythmias.
Triggered automaticity is caused by afterdepolarizations. These
are oscillations in the membrane potential that occur during or after
repolarization. Oscillations large enough to reach threshold initiate premature
action potentials and thus heart beats (Figure 48a). This may occur repeatedly,
initiating a sustained arrhythmia either directly or by triggering re-entry
(see below). After depolarization magnitude is influenced by changes in heart
rate, catecholamines and parasympathetic withdrawal.
Early afterdepolarizations (EADs) occur during the terminal plateau or
repolarization phases of the action potential. They develop more readily in
Purkinje fibres than in ventricular or atrial myocytes. EADs can be induced by
agents that prolong action potential duration and increase the inward current.
For example, drugs such as sotalol which block K+ currents can cause
EADs and triggered activity by delaying repolarization, especially when the
heart rate is slow. The abnormal rhythms induced by such drugs resemble torsade
de pointes, a type of congenital arrhythmia.
Delayed afterdepolarizations (DADs) occur after repolarization is complete, and
are caused by excessive increases in cellular [Ca2+]. DADs can be
caused by catecholamines, which increase Ca2+ influx through the L-type
Ca2+ channel, and by digitalis glycosides, which increase [Ca2+]i
(see Chapter 47). They can also occur in heart failure, in which myocyte Ca2+
regulation is impaired. The oscillation of membrane potential following the
increase in [Ca2+]i is caused by a transient inward
current involving Na+ occurrence and magnitude of DADs and the
likelihood that they will cause arrhythmias is increased by conditions that
enhance this current. These include increased Ca2+ release from the
sarcoplasmic reticulum and longer action potentials, which cause larger increases
in [Ca2+]i. Therefore, drugs prolonging action potential
duration may trigger DADs, whereas drugs shortening the action potential have
the opposite effect. The magnitude of the transient inward current is also
influenced by the resting membrane potential, and is maximal when this is
approximately −60 mV.
Re-entry occurs when an impulse that
is delayed in one region of the myocardium re-excites adjacent areas of the
myocardium more than once. The initiating impulse is often premature, for
example having resulted from triggered automaticity. One type of re-entry,
termed anatomical, requires the presence of three conditions:
· There must
exist an anatomical circuit around which the impulse can circulate (a process
termed circus movement). This circuit can utilize parallel conduction
pathways such as two Purkinje fibre branches, or the AVN and an accessory
atrioventricular conduc- tion pathway.
· Impulse
conduction at some point in the circuit should be slow enough to allow the
region in front of the impulse to recover from refractoriness. This region is
termed the excitable gap.
· The circuit
must also include a zone of unidirectional block where conduction is blocked in
one direction while remaining possible in the other.
Wolff–Parkinson–White (WPW)
syndrome is an uncommon
supraventricular arrhythmia (population incidence 0.1–0.2%) which provides a
prototypical example of anatomical re-entry (see Chapter 49). People with WPW
have a congenital accessory (extra) conduction pathway (formerly termed the bundle
of Kent) between an atrium and ventricle, which is often situated on the
left free wall of the heart. Thus, as shown in Figure 48b, normal atrial depo-
larization (black arrows) is conducted to the ventricles through both the AVN and the
accessory pathway (blue arrows). The accessory pathway has properties differing
from that of the AVN. First, it conducts more rapidly than the AVN, so
the part of the ventricle to which the pathway connects depolarizes before the
rest (pre-excitation), resulting in a widened QRS complex. Secondly, the
accessory pathway has a longer refractory period than the AVN. Thus, if
a premature impulse arises in an atrium (red arrows), it may be conducted
normally to the ventricles via the AVN (1 in Figure 48), but may not be
conducted forwards through the accessory pathway, which is still refractory
from the previous impulse (2). However, when the impulse through the AVN
is dis- tributed to the ventricles (3), it will encounter the distal end
of the accessory pathway (4) which has now had time to recover its
excit- ability, and will be conducted backwards through this pathway into the
atrium (5). It can then traverse the AVN again and continue to cycle
though the anatomical circuit encompassing the AVN, His–Purkinje system,
ventricles, accessory pathway and atrium (1–3–4–5).
The ventricles are excited with each circuit, which causes a tachycardia
because the impulse cycles more quickly than the SAN spontaneously depolarizes.
It is noteworthy that the ‘border
zone’ between healthy myocardium and the scar resulting from the healing of a myocardial
infarct (see Chapter 44) typically contains a mixture of living muscle cells
and connective tissue. In some cases, a narrow band (‘isthmus’) of still-viable
muscle cells spans an area of non-conducting scar, thereby connecting two
regions of healthy myocardium (Figure 48c). Conduction of the impulse by the
isthmus may be slowed or even demonstrate effective unidirectional block
because this tissue takes so long to recover its excitability between action
potentials. This arrangement provides conditions analogous to those that WPW
(think of the isthmus as playing the part of the accessory pathway and the
healthy myocardium to the side of the non-conducting scar as mimicking the
AVN), and is thought to cause many ventricular arrhythmias arising in patients
following myocardial infarct healing.
Functional re-entry does not require an anatomically defined circuit,
and tends to arise when conduction is impaired or repolarization is delayed in
a region of myocardium, usually as result of ongoing ischaemia or damage from a
previous myocardial infarction. Under these conditions, the firing of frequent
or premature impulses can cause the front of one wave of depolarization to
collide with the tail of the preceeding wave where it has been slowed (Figure
48d). The second wave is unable to proceed into the region of the myocardium
that is still refractory, but at the edges of this region it curls into itself,
forming twin ‘whirlpools’ of depolarization, termed rotors. Rotors can
similarly form under some conditions if an impulse collides with a structural
obstacle such as a scar. Once formed, rotors may persist and continue to emit
spiral waves of depolarization with a frequency determined by the rotation
period of the spiral; these excite the heart and cause tachycardia. The
formation of such spiral waves, and the further fragmentation of the waves of
depolarization they generate, is thought to underlie the genesis of the chaotic
electrical activity that results in the total loss of atrial or ventricular
coordinated contrac- tion termed fibrillation (see Chapters 49 and 50).
The sympathetic nervous system and
arrhythmias
Sympathetic stimulation of the heart
results in results in a variety of β-receptor mediated effects enabling
positive chronotropy and inotropy (see Chapters 12 and 13). These include the
acceleration of impulse generation and conduction by the SA and AV nodes,
respectively. In cardiac muscle cells Ca2+ influx and release are
facilitated leading to an increased rise in [Ca2+]i
during the action potential, and the activities of multiple ion channels are
modulated in such a way as to enhance conduction and decrease refractoriness.
These effects are crucial for the normal tuning of cardiac function, but
excessive sympathetic stimulation of the heart during myocardial infarction, or
in the context of cardiac scarring, ischemia, chronic heart failure or
cardiomyopathy, can be arrhythmogenic. The reasons for this are not well
understood, but may relate to observations that the myocardium is innervated more
densely in some areas than in others and that ion channel expres- sion also
varies between different parts of the ventricles. Thus, sympathetic activation
may exaggerate intrinsic regional inhomogeneities in conduction velocity and
refractoriness. These effects are likely to promote triggered automaticity and
functional reentry and therefore tachycardia and fibrillation.
