This document discusses cardiac action potentials and the mechanisms of arrhythmogenesis. It describes the five phases of the cardiac action potential and three phases of the pacemaker potential. Various mechanisms that can cause arrhythmias are explained, including abnormal automaticity, triggered activity due to early or delayed afterdepolarizations, and disorders of impulse conduction such as block, reentry, and decremental conduction. Specific cardiac arrhythmias like atrial flutter, atrial fibrillation, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are also discussed.

1. SEMINAR

2. Cardiac Action Potential
• Five phases in cardiac muscle
• RMP of mucle cell is -90mV.
• Phase 0 – Rapid depolarisation ; Na+ channel
are triggered to open, transient inward
current resulting in depolarisation
• Phase 1 - Early rapid repolariastion .
Na+ channels are inactivated ; fast and slow
potassium channels are activated [Ito]

3. • Phase 2 – plateau phase calcium influx against
potassium efflux.
• Phase 3 – Rapid repolarisation ; result from
inactivation of inward calcium channel and
activation of delayed rectified potassium
channels.
• Phase 4 – Resting membrane potential

5. PACEMAKER POTENTIAL
• 3 phases
• Resting
membrane
potential -50 to-
60 mv

7. Action potentials recorded from different tissues in the heart

9. MECHANISM OF ARRHYTHMOGENESIS
MECHANISM
DISORDERS OF
IMPULSE
FORMATION
TRIGGERED
ACTIVITY
DAD
EAD
ABNORMAL
AUTOMATICITY
BOTH
COMBINED
DISORDERS OF
IMPULSE
CONDUCTION
BLOCK
TACHYCARDIA
DEPENDENT
DECELERATION
DEPENDENT
RENTRY
ANATOMICAL
FUNCTIONAL

10. Normal Automaticity
Membrane clock
• HCN channels
• If –funny current
• Conduct both Na
and K inward
• Activated by
repolarisation
Calcium clock
• Periodic sub
membrane
increases in Ca2+.
• Activates NCX
channel – inward
current.
• Intra cellular signals
thus converted to
membrane voltage
signals

11. DISORDERS OF IMPULSE FORMATION
• Inappropriate discharge rate of the normal
pacemaker (too fast or too slow for physiologic
needs of patient),
• Discharge of an ectopic pacemaker either as
escape rhythm or accelerated automaticity.
• Pacemaker discharges from ectopic sites usually
kept from reaching the level of threshold
potential because of overdrive suppression by the
more rapidly firing sinus node .

12. ABNORMAL AUTOMATICITY
• Abnormal automaticity can arise from cells
that have reduced maximum diastolic
potentials [positive to −50 mV].
• Rhythms resulting from abnormal
automaticity
– slow atrial, junctional, or ventricular escape
rhythms;
– certain types of atrial tachycardias (ATs),
accelerated junctional rhythms.

13. TRIGGERED ACTIVITY
• Triggered activity is initiated by
afterdepolarizations, which are depolarizing
oscillations in membrane voltage.
• termed Early afterdepolarizations [EAD]when
they arise before full repolarization of the AP ;
• Delayed afterdepolarizations (DAD) when they
occur after completion of repolarization
(phase 4).

14. Delayed Afterdepolarizations
• DADs result from the activation of a calcium-sensitive
inward current due to aberrant diastolic Ca2+ release.
• The duration and amplitude of Ca2+ efflux from the SR
are tightly controlled by the gating of RyR2 channels.
– Increased catecholamine release due to adrenergic
stimulation.
– Reduced FKBP-12.6 [regulatory protein ] binding has been
implicated in cardiac arrhythmogenesis associated with
heart failure.
– The IP3 receptor (IP3R) is another Ca2+-release channel in
cardiomyocytes are upregulated in heart failure and AF.

16. • Calmodulin kinase type-II (CaMKII) is a key player in
promoting DADs, via phosphorylation of multiple
membrane proteins.
• Intracellular Na+ is exchanged for Ca2+, drugs that
reduce INa suppress Na+ load and, indirectly, Ca2+ load,
NCX current, and DADs.
• Overdrive pacing increase the amplitude and shorten
the cycle length of DADs after cessation of pacing
(overdrive acceleration), because they enhance cellular
Ca2+ loading.
• Hence DAD-triggered activity may not be suppressed
easily or indeed may be precipitated by rapid rates.

17. Early Afterdepolarizations
• Conditions that cause delayed repolarisation.
• Seen in the acquired and congenital forms of LQTS.
• When the AP is excessively prolonged, the membrane
potential remains at levels that allow recovery of
enough steady-state Ca2+ (particularly during phase 2)
or Na+ (during phase 3) current to depolarize the cell,
producing an EAD.
• Can initiate tachyarrhythmias either by the induction of
unstable transmural reentry or via repetitive rapid
EADs.

18. • Sympathetic stimulation can increase EAD amplitude to
provoke ventricular tachyarrhythmias.
• Acquired LQTS and torsades de pointes from class III
antiarrhythmic and non-cardiac agents like cisapride,
erythromycin, moxifloxacin, and psychoactive drugs,
likely mediated by EADs.
• EAD-associated APD prolongation increases Ca2+ influx
and produces Ca2+ loading in the SR, thus increasing
the likelihood of DAD generation. Thus, EADs and DADs
may occur together with common initiating conditions

19. Disorders of Impulse Conduction
• Conduction delay and block can result in
bradyarrhythmias or tachyarrhythmias.
• Bradyarrhythmias occur when the propagating
impulse is blocked and is followed by asystole
or a slower escape rhythm;
• Tachyarrhythmias occur when the delay and
block produce reentrant excitation .

20. • DECELERATION-DEPENDENT BLOCK
– Reduced spontaneous diastolic depolarisation.
– However, excitability and the speed of impulse
propagation increase as the membrane depolarizes
• TACHYCARDIA-DEPENDENT BLOCK
– Impulses are blocked at rapid rates or short cycle
lengths
– Occur as a result of incomplete recovery of
refractoriness – Post repolarization refractoriness.
– functional bundle branch block.

21. REENTRY
• various names— reentry, reentrant excitation,
circus movement, reciprocal or echo beat, and
reciprocating tachycardia.

22. Anatomical Reentry
• Discrete anatomical barrier separating
alternate conduction pathways.
• In many, AV node behaves as if there are two
functionally independent pathways
• Typically, the pathway with the faster
conduction has a longer RP.

23. • Alternative conducting pathways separated
longitudinally but with connections at each end;
• Different Refractory Periods of the alternate
pathways .
• The maintenance of anatomic reentry requires
the existence of an “excitable gap,”
• Anatomic reentry occurs in patients with Wolff-
Parkinson-White (WPW) syndrome, in AV nodal
reentry, in some atrial flutters, and some VTs.

25. Functional Reentry
• Lacks confining anatomic boundaries
• Functionally different electrophysiologic
properties caused by local differences in
transmembrane AP.
• Failing heart or infarct border zone or acutely
ischemic myocardium.
• Spiral wave rotor

27. Specific Arrhythmias
Atrial Flutter
• Reentry
• Counterclockwise in a caudocranial direction
in the interatrial septum and in a craniocaudal
direction in the right atrial free wall

28. Atrial Fibrillation
• Multiple disorganized reentrant waves
• EPS shown that both reentrant and non
reentrant mechanisms (automaticity and
triggered activity) may underlie initiation of AF
from the PVs.
• Familial AF - Mutations in subunits of the
delayed rectifier potassium channel and the
voltage-gated sodium channel

29. Brugada Syndrome
• Congenital sudden death syndrome
• m/c genetic abnormalities - LOF in SCN5A .
• Brugada syndrome–associated gene defects
cause a reduction or loss of sodium or calcium
current in combination with altered functional
properties of voltage-gated sodium channels

30. Catecholaminergic Polymorphic Ventricular Tachycardia
• Inherited arrhythmogenic syndrome characterized by
stress-induced, adrenergically mediated polymorphic
VT occurring in structurally normal hearts .
• Spontaneous diastolic Ca2+ leak from the SR via RyR2,
leading to intracellular Ca2+ waves and triggered
activity .
• RyR2 mutations - 95% of cases.
• Mutations in genes encoding calsequestrin,
calmodulin, and triadin

31. Arrhythmogenic Right Ventricular Cardiomyopathy
• Inherited myopathy , sustained monomorphic VT and
sudden death
• Mutations in the desmosomal proteins, intercalated
disk proteins, nuclear envelope proteins, along with
desmin, titin, phospholamban, channel proteins, and
growth factors
• 20% to 45% mutations - gene encoding plakophilin 2 .
– Loss of PKP2 expression reduces the voltage-gated sodium current and
connexin 43 expression at the intercalated disc and thus results in slowed
AP propagation.

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41. • DECREMENTAL CONDUCTION
– Phenomenon where an impulse loses activation
effectiveness as it spreads anterogradely.
– Seen in the AV node, in relation to the relatively
small amplitude of phase 0 Ca2+ current in slow
channel tissue, especially at fast rates and in the
presence of disease.
– Associated with increased risk of conduction
block.