The document discusses ion channels and their role in generating cardiac action potentials. It begins by defining ion channels as pore-forming proteins that gate the flow of ions across cell membranes. It then describes the key properties of ion channels including selectivity, gating, and their role in establishing membrane potentials. The remainder of the document details the specific ion channels involved in each phase of the cardiac action potential, including the fast sodium current underlying the upstroke in Phase 0, the potassium and chloride currents producing Phase 1 repolarization, the calcium and potassium currents maintaining the Phase 2 plateau, and the currents responsible for Phase 3 repolarization. Pacemaker cell action potentials are also discussed, noting their unique pacemaker potential in Phase 4 and lack of Phase

1. CARDIAC ION CHANNELS
AND ION CHANNELOPATHIES

2. What are Ion Channels ?
• Ion channels Ion channels are pore-forming membrane
proteins whose function is establishing a resting membrane
potential, shaping action potentials and other electrical signals
by gating the flow of ions across the cell membrane,
controlling the flow of ions across membranes, and regulating
cell volume.
• Ion channel - properties
– Selectivity: Each specific ion crosses through specific channels
– Gating: transition between states (closed ↔ open ↔Inactivation)
Voltage-gated ; Ligand-gated
– Channels mediate ion movement down electrochemical
gradients.
– Activation of channel permeable to ion X shifts membrane
potential towards to its Equilibrium Potential, EX

3. Equilibrium Potential or Nernst
PotentialThe voltage at which there is zero net flux of a given
ion (Electrical gradient = a chemical concentration
gradient)
For K+ : ~ -90 mV
K current (IK1) is the major contributor for

4. • The generation of the action potential and the regional differences
that are observed throughout the heart are the result of the
selective permeability of ion channels distributed on the cell
membrane.
• During the action potential, the permeability of ion channels
changes and each ion, eg, X, moves passively down its
electro- chemical gradients (ΔV=[Vm-Vx,] where Vm is the
membrane potential and Vx the reversal potential of ion X) to
change the membrane potential of the cell.
• The electrochemical gradient determines whether an ion moves
into the cell (depolarizing current for cations) or out of the
cell (repolarizing current for cations).
• Homeostasis of the intracellular ion concentrations is maintained by
active and coupled transport processes that are linked directly or
indirectly to ATP hydrolysis.

5. • Ion channels do not function as simple fluid-filled pores, but
provide multiple binding sites for ions as they traverse
the membrane.
• Ions become dehydrated as they cross the membrane as ion-
binding site interaction is favored over ion–water interaction.
• Like an enzyme–substrate interaction,the binding of the
permeating ion is saturable.
• Most ion channels are singly occupied during permeation; certain K
channels may be multiply occupied.
• The equivalent circuit model of an ion channel is that of a resistor.
• The electrochemical potential, V is the driving force for
ion movement across the cell membrane.

6. • Simple resistors have a linear relationship between V and
current I (Ohm’s Law, I=ΔV/R=ΔVg, where g is the channel
conductance).
• Most ion channels have a nonlinear current-voltage
relationship.
• For the same absolute value of V, the magnitude of
the current depends on the direction of ion movement into
or out of the cells.
• This property is termed rectification and is an
important property of K+ channels, they pass little outward
current at positive (depolarized) potentials.
• The molecular mechanism of rectification varies
with ion channel type

7. Ion permeation
•describes the movement through the open channel.
•The selective permeability of ion channels to specific ions is a
basis of classification of ion channels (eg, Na, K, and Ca2
channels).
•Size, valency, and hydration energy are important
determinants of selectivity.
•The selectivity ratio of the biologically important alkali cations
is high. For example, the Na:K selectivity of sodium channels is
10:1.

8. GATING
•mechanism of opening and closing of ion channels and is their second
major property.
•Ion channels are also subclassified by their mechanism of gating:
•Voltage dependent,
• ligand-dependent, and
•mechano-sensitive gating.

9. Ion channels have 2 mechanism of closure.
•Certain channels like the Na+ and Ca2+ channels enters a closed
inactivated state during maintained depolarization.
•To regain their ability to open, the channel must undergo a recovery process at
hyperpolarized potentials.
•The inactivated state may also be accessed from the closed state.
•Inactivation is the basis for refractoriness in cardiac muscle and is
fundamental for the prevention of premature re-excitation.
•If the membrane potential is abruptly returned to its hyperpolarized (resting) value
while the channel is open, it closes by deactivation, a reversal of the normal
activation process.

10. LIGAND-DEPENDENT GATING
•second major gating mechanism of cardiac ion channels.
•The most thoroughly studied channel of this class is the acetylcholine
(Ach)-activated K channel.
•Acetylcholine binds to the M-2 muscarinic receptor and activates a G
protein–signaling pathway, culminating in the release of the subunits Gαi
and Gβγ.
• The Gβγ subunit activates an inward-rectifying K channel, IKAch
that
abbreviates the action potential and decreases the slope of diastolic
depolarization in pacemaker cells.
• IKAch
channels are most abundant in the atria and the SA and
atrioventricular nodes.
•IKAch activation is a part of the mechanism of the vagal control of the
heart.
•The ATP-sensitive K+ channel, also termed the ADP-activated K+ channel,
is a ligand-gated channel distributed abundantly in all regions of the
heart.
inward-rectifying K+channel

11. Ion channels in the heart
♦ Sodium channels – voltage gated and ligand
gated
♦ Potassium channels - voltage gated, inward
rectifier and background channels
♦ Calcium channels – transient and long
lasting

12. Physiology of Ion Channels
♦ Electrical signaling in the heart involves the
passage of ions through ionic channels.
♦ The Na+, K+, Ca2+, and Cl− ions are the
major charge carriers.
♦ Their movement across the cell membrane
creates a flow of current that generates
excitation and signals in cardiac myocytes.

14. Cardiac Membrane currents that generate
the normal action potential
Basic Science for the Clinical Electrophysiologist:
Cardiac Ion Channels Augustus O. Grant

16. Phase 4
• Represents resting membrane potential
membrane potential when the cell is not
stimulated.
• this phase will be a horizontal line
• caused by the difference in ionic
concentrations and conductances across the
cell membrane
• normal resting membrane potential in the
ventricular myocardium is about -85 to -95 mV

17. Phase 4
♦ Because cardiac myocytes have an abundance of open K+
channels at rest, the cardiac transmembrane potential (in phase
4) is close to EK.
♦ Potassium outward current through open, inwardly rectifying
K+ channels (IKl) under normal conditions contributes to the
resting membrane potential mainly in atrial and ventricular
myocytes, as well as in Purkinje cells.
♦ Calcium does not contribute directly to the RMP, but changes
in intracellular free calcium concentration can affect other
membrane conductance values.

18. ♦For example, an increase in (SR) Ca2+ load can cause spontaneous intracellular Ca2+
waves, which in turn activate the Ca2+-dependent chloride conductance ICl.Ca and
thereby lead to spontaneous transient inward currents and concomitant membrane
depolarization
♦Increases in [Ca2+]i can also stimulate the Na+/Ca2+ exchanger INa/Ca. This
protein exchanges three Na+ ions for one Ca2+ ion; the direction is dependent on the
sodium and calcium concentrations on the two sides of the membrane and the
transmembrane potential difference.
♦At RMP and during a spontaneous SR Ca2+ release event, this exchanger would
generate a net Na+ influx, possibly causing transient membrane depolarizations
♦[Ca2+]i has also been shown to activate IKl in cardiac myocytes, thereby indirectly
contributing to cardiac RMP
♦Because of the Na-K pump, which pumps Na+ out of the cell against its
electrochemical gradient and simultaneously pumps K into the cell against its chemical
gradient, the intracellular K+ concentration remains high and the intracellular Na+
concentration remains low.
♦ This pump, fueled by an Na+,K+-ATPase enzyme that hydrolyzes ATP for energy, is
bound to the membrane. It requires both Na+ and K+ to function and can transport
three Na+ ions outward for two K+ ions inward. Therefore the pump can be
electrogenic and generate a net outward movement of positive charges.

19. Phase 0
♦ The upstroke of the cardiac AP in atrial and ventricular muscle and
His-Purkinje fibers is the result of a sudden increase in membrane
conductance of Na+
♦ An externally applied stimulus or a spontaneously generated local
membrane activates enough Na+ channels, Na+ ions enter the cell
down their electrochemical gradient. The excited membrane no
longer behaves like a K+ electrode, that is, exclusively permeable to
K+, but more closely approximates an Na+ electrode, and the
membrane moves toward the Na+ equilibrium potential.
♦ The rate at which depolarization occurs during phase 0, that is,
the maximum rate of change in voltage over time, is indicated
by the expression dV/dtmax or V􏰀max , which is a reasonable
approximation of the rate and magnitude of Na+ entry into the cell
♦ The transient increase in sodium conductance lasts 1 to 2

20. ♦ The action potential, or more properly the Na+ current
(INa), is said to be regenerative; that is, intracellular
movement of a little Na+ depolarizes the membrane more,
which increases conductance of Na+ more and allows
more Na+ to enter, and so on
♦ When the equilibrium potential for Na+ (ENa) is reached,
Na+ no longer enters the cell; that is, when the driving
force acting on the ion to enter the cell balances the
driving force acting on the ion to exit the cell, no current
flows.

21. Upstroke of the Action Potential
♦ In normal atrial and ventricular muscle and in fibers in the His-
Purkinje system, action potentials have very rapid upstrokes with a large
V􏰀max and are called fast responses
♦ Action potentials in the normal sinoatrial and AV nodes and many types
of diseased tissue have very slow upstrokes with a reduced V􏰀max and
are called slow responses.
♦ Upstrokes of slow responses are mediated by a slow inward,
predominantly L-type voltage-gated (Cav) Ca2+ current (ICa.L)
rather than by the fast inward INa. These potentials have been termed
slow response potentials because the time required for activation and
inactivation of the slow inward current (ICa.L) is approximately an
order of magnitude slower than that for the fast inward Na+ current
(INa).
♦ Recovery from inactivation also takes longer. Calcium entry and
[Ca2+]i help promote inactivation.
♦ The slow channel requires more time after a stimulus to be reactivated.

22. ♦ In fact, recovery of excitability outlasts full restoration of
maximum diastolic potential, which means that even
though the membrane potential has returned to normal, the
cell has not recovered excitability completely because the
latter depends on the elapse of a certain amount of time
(i.e., is time dependent) and not just on recovery of a
particular membrane poten- tial (i.e., voltage dependent), a
phenomenon termed postrepolarization refractoriness.

23. Differences Between Channels
♦ Fast and slow channels can be differentiated on the basis of their pharmacologic
sensitivity. Drugs that block the slow channel with a fair degree of specificity
include verapamil, nifedipine, diltiazem, and D-600 (a methoxy derivative of
verapamil).
♦ Antiarrhythmic agents such as lidocaine, quinidine, pro- cainamide, and
disopyramide affect the fast channel and not the slow channel.
♦ Normal action potentials recorded from the sinus node and the compact node
of the AV junction have a reduced resting membrane potential, action
potential amplitude, overshoot, upstroke, and conduction velocity when
compared with action potentials in muscle or Purkinje fibers
♦ Slow-channel blockers suppress sinus and AV nodal action potentials. The
prolonged time for reactivation of ICa.L probably accounts for the fact that
sinoatrial and AV nodal cells remain refractory longer than the time that it
takes for full voltage repolarization to occur. Therefore slow conduction and
prolonged refractoriness are characteristic features of nodal cells. These cells also
have a reduced “safety factor for conduction”, which means that the stimulating
efficacy of the propagating impulse is low and conduction block occurs easily.

24. Inward Currents
♦ INa and ICa.L represent two important inward currents. Another
important inward current is If, also called the pacemaker or
“funny” current.
♦ activated by hyperpolarization and is carried by Na+ and K+.
♦ It generates phase 4 diastolic depolarization in the sinoatrial
node.
♦ If modulation is one major mechanism whereby beta-adrenergic and
cholinergic neurotransmitters regulate cardiac rhythm under
physiologic conditions.
♦ Catecholamines increase the probability of channel opening by
shifting the channel’s activation curve to more positive potentials,
which leads to increased current availability for the generation of
diastolic depolarization and hence steepens its rate.
♦ Cholinergic action, in general, exerts the opposite effect.

25. Phase 1
♦ Following phase 0, the membrane repolarizes rapidly and
transiently to almost 0 mV (early notch), partly because of
inactivation of INa and concomitant activation of several
outward currents.
♦ The transient net outward current causing the small
downward deflection of the action potential is due to the
movement of K+
and Cl-
ions, carried by the Ito1 and
Ito2 currents respectively

26. ♦ Ito currents determine the
amplitude and the timing
of Ca2+ release from the
SR.
♦ Ito currents express
differentially at different
parts of heart
♦ Maximum in RV, basal
region and
epicardium
Action potential plots demonstrating differences in the action
potential shape of human ventricular myocytes of
subepicardial (A) and subendocardial (B) ori- gin.
Subepicardial myocytes present a prominent notch during
phase 1 repolarization of the action potential, most likely
caused by a larger I
to
in these cells. The notch is absent in
subendocardial cells. The peak plateau potential is higher in

27. Phase 2
♦ "plateau" phase of the cardiac action potential (absent in
pacemaker cells)
♦ sustained by a balance between inward movement of
Ca2+
(ICa) through L-type calcium channels and outward
movement of K+
through the slow delayed
rectifier potassium channels - IKs

28. Phase 3
• repolarization proceeds rapidly at least in part because of
two currents: time-dependent inactivation of ICa.L, with a
decrease in the intracellular movement of positive charges, and
activation of repolarizing K+ currents, including the slow
and rapid components of the delayed rectifier K+ currents IKs
and IKr and the inwardly rectifying K+ currents, which all
cause an increase in the movement of positive charges out of
the cell.
• The net membrane current becomes more outward, and the
membrane potential shifts to the resting potential. A small-
conductance Ca2+-activated K+ current, IK.Ca, is expressed in
human atrial myocytes, where it controls the time course of
phase 3 repolarization

29. Action Potential of the pacemaker
cells
• The pacemaker cells do not have a stable
resting membrane potential like the nerve and
the skeletal muscles.
• Instead they have an unstable membrane
potential that starts at – 60mv and slowly drifts
upwards towards threshold.
• Because the membrane potential never rests at
a constant value, it is called a Pacemaker
Potential rather than a resting membrane
potential.
• Phase 1 and 2 typically absent.

30. IONIC BASIS OF ACTION
POTENTIAL OF
PACEMAKER CELLS
Phase 4: Pacemaker Potential:
•Opening of voltage-gated Sodium
channels called Funny channels (If or f
channels ).
•Closure of voltage-gated Potassium
channels.
•Opening of Voltage-gated Transient-
type Calcium (T-type Ca2+
channels)
channels .
Phase 0: The Rising Phase or
Depolarization:
•Opening of Long-lasting voltage-gated
Calcium channels (L-type Ca2+
channels).
•Large influx of Calcium.
Phase 3: The Falling Phase or
Repolarization:
•Opening of voltage-gated Potassium
channels
•Closing of L-type Ca channels.
•Potassium Efflux.

31. ♦ Six currents participates in pacemaker
potential:
Four inward currents
1- funny current (If) 
Depolarize the membrane to threshold of L&T
type ca channel
2-T -type Ca channel :
♦ opening of T-type channels can depolarize the
cells
further toward the threshold for L-type
channels
because T channels have lower threshold.

32. 3-L -type Ca channel : contribute to late part of
pacemaker potential &is the major depolarizing
force during phase 0
4-Na-Ca exchanger  operates because of Ca
inside cardiac muscles due to previous Ca
channels
Two outward K currents
1-delayed rectifying K channels(Ik)
2-I K.Ach

33. (funny, If)
I-Called Funny channels because of unusual property :
1-If is a slowly nonselective cation current activating i.e., it
is carried by a mixture of both Na+ and K+ ions .
2-If is a inward depolarizing current
activated by hyperpolarisation
II-Called HCN (Hyperpolarization-activated cyclic
Nucleotide-gated)
because it is activated by
hyperpolarization & modulated by cAMP

35. CARDIAC AP – types
Fast channel AP Slow channel AP
Site Atria , Ventricle, Purkinje
fibre
SA node, AV node, around
AV ring and coronary sinus
opening
Predominant ion in
phase 0
Sodium Calcium
Activation potential -60 to -70 -40 to -55
Conduction velocity 0.5 - 5.0 m/s 0.01 – 0.1 m/s

36. Sodium channel (hNav1.5)
♦ Gene (SCNA5) located on chr. 3
♦ Responsible for depolarization
♦ Rapid activation followed by rapid inactivation
♦ Alpha and beta subunit

37. • Each domain contains six transmembrane segments (S1–S6).
• S4 segments are held responsible for voltage-dependent activation.
• At the end of phase 0, most channels are inactivated and can be
reactivated only after recovery from inactivation during phase 4.
• Some channels remain open or reopen during phases 2 and 3, and
they carry a small late Na􏰃 current (INaL).
• Despite its minor contribution in healthy hearts, INaL may play an
important role in diseased hearts.
• Cardiac Na􏰃 channels are blocked by high concentrations of
tetrodotoxin. Their gating properties usually are studied by
expression of SCN5A in heterologous systems (e.g., Xenopus oocytes
or human embryonic kidney cells).
• INa amplitude increases and its gating properties accelerate when
SCN5A is co-expressed with its 􏰃-subunits

38. Mutations of sodium channels:
Inherited diseases
♦ Gain of function mutation
– LQT3 mutations in SCN5A delay
repolarization, mostly by enhancing INaL
♦ Loss of function
– Brugada syndrome (BrS1)
– Idiopathic VF
– Progressive cardiac conduction disease
– Congenital sick sinus syndrome

39. Delayed repolarization may trigger early afterdepolarizations (EADs; abnormal depolarizations
during phase 2 or 3 due to reactivation of L-type Ca2􏰃 channels).
EADs are believed to initiate torsades de pointes.
Accordingly, drugs that block INaL (e.g., ranola- zine, mexiletine) may effectively shorten
repolarization in LQT3 patients.

40. ♦ Moreover, mutations in genes encoding Na􏰃
channel regulatory proteins may cause rare
types of LQTS , indicating the importance of
these proteins for normal channel function.

41. Brugada syndrome
♦ First described in 1992
♦ About 20% deaths in structurally normal hearts
♦ 90% affected are males
♦ High incidence in SE Asia (≥5/10,000)
♦ Mean age at diagnosis 40±22 yrs (2 days-84yrs)
♦ sudden death typically occurring during sleep.
♦ also been demonstrated in children and infants

42. BRUGADA SYNDROME
♦ is traditionally linked to mutations in SCN5A
that reduce INa by different mechanisms

43. ♦ Characterized by prolonged
conduction intervals, right
precordial ST-segment
elevation(V1-V3) and
increased risk for
ventricular tachyarrhythmia.
Prolonged conduction
intervals are attributed to
conduction slowing due to
INa reduction
♦ ST-segment elevation is
hypothesized to be due to
preferential conduction
slowing in the right
ventricle and/or aggravation
of transmural voltage
gradients (AP shortening in
epicardial but not
endocardial myocytes

44.  Recently, Brugada syndrome has also been linked to mutations in
genes encoding Na􏰃 channel beta􏰃-sub- units or a protein involved
in intracellular Nav1.5 trafficking
 Use of Na􏰃 channel blocking drugs may evoke or aggravate Brugada
syndrome and is discouraged in patients (suspected of) having
Brugada syndrome.

45. Diagnosis:

46. Diagnosis: (contd.)
♦ Type 1 ST segment elevation with any one of the
following:
– Documented VF,
– Polymorphic ventricular tachycardia (VT);
– Family history of SCD (<45 years old);
– Coved-type ECGs in family members;
– Inducibility of VT with EPS;
– Syncope; or
– Nocturnal agonal respiration
♦ Type 2/3 ECG becomes type 1 on challenge with
Na-channel blockers, along with any of the above
clinical conditions

47. ♦ Type 1 ECG is labile
♦ Diagnosis is improved by placing right precordial leads
higher in 2nd
/3rd
IC space
♦ Test terminated if
– the diagnostic Type 1 ST-segment elevation,
– ST segment in Type 2 increases by ≥2 mm;
– premature ventricular beats or other arrhythmias
develop;
– QRS widens to ≥130% of baseline.

48. Genotype-phenotype correlation:
♦ Autosomal dominant mode of transmission
♦ 18-30 % pts have a loss of function
mutation in SCNA5 (>100 mutations
described )
♦ Mutations do not identify a subset at higher
risk of cardiac events

49. Risk stratification (symptomatic pts)
♦ Highest risk
– Presenting with aborted SCD (69% at 54±54 mths
– Syncope with spontaneous type 1 ECG (19% at 26±36
mths)
♦ Meta analysis of 1545 pts by Gehi et al revealed a
event rate of 10% at 32 mths
– h/o syncope/SCD
– Spontaneous Type 1 ECG
– Male gender

50. Risk stratification (asymptomatic pts)
♦ Controversy-
– 1998- brugada et al reported event rate of 27% over 34
mths (10%/yr)
– 2002 same authors- 8 % over 27 ± 29 mths (8%/yr)
– 2005- same authors-6% over 42 ± 42 months (1.7%/yr)
– 2005-Eckardt et al reported 0.8% over 40± 50 mths
(0.24%/yr)
♦ role of EPS is controversial (brugada et al showed
it to have a high negative predictive value)

51. MANAGEMENT
 There is no exact treatment modality that reliably and totally
prevents ventricular fibrillation from occurring in this
syndrome
 treatment lies in termination of this lethal arrhythmia before
it causes death.
 Quinidine , a pharmaceutical agent that acts as a class I
antiarrhythmic agent is used.
 Test Dose: 200 mg PO quinidine sulfate several hr before full
dosage
 AFib: 300-400 mg PO q6hr
 PSVT: 400-600 mg PO q2-3hr until paroxysmterminated
 Atrial/Ventr Premature Contractions: 200-300 mg PO
TID/QID,Maint: 200-400 mg PO

53. 1. Cardiac conduction disease is manifested by progressive
conduction defects at the atrial, atrioventricular, and/or
ven- tricular level and is commonly associated with
SCN5A mu- tations that are also linked to Brugada
syndrome. How a single mutation may cause different
phenotypes or combinations thereof is often not known.
2. Dilated cardiomyopathy is a familial disease with
ventricular dilation and failure. The few reported cases
with SCN5A mutation display atrial and/or ventricular
arrhythmia. Dilated cardiomyopathy–linked SCN5A
mutations cause divergent changes in gating, but how such
changes evoke contractile dysfunction and arrhythmia is
not understood.
3. Finally, mutations in SCN5A have occasionally been
linked to sick sinus syndrome, which includes sinus
bradycardia, sinus arrest, and/or sinoatrial block. SCN5A
mutations may impair sinus node function by slowing AP
depolarization or prolonging AP duration in SAN cells.

54. Acquired diseases
♦ INa reduction and/or INaL increase may contribute to
arrhythmogenesis in acquired diseases.
♦ In atrial fibrillation (AF), chronic tachyarrhythmia alters
expression levels of several ion channels in atrial myocytes,
which may promote and maintain AF (“electrical remodeling”).
♦ Nav1.5 expression is reduced as part of this process, leading to
INa reduction.
♦ Moreover, AF (either familial or secondary to cardiac diseases
[nonfamil- ial]) is linked to both SCN5A loss-of-function
mutations and gain-of-function mutations.
♦ INa loss of function may pro voke AF by slowing atrial electrical
conduction, whereas gain of function may induce AF by
enhancing spontaneous excitability of atrial myocytes.

55. ♦ In heart failure, peak INa is reduced, while INaL is
increased.
♦ Decreased SCN5A expression may underlie peak INa
reduction. INaL increase is attributed to increased
phosphorylation of Na􏰃 channels, when intracellular
Ca2􏰃 in heart failure rises.
♦ In myocar- dial infarction, myocytes in the surviving
border zone of the infarcted area exhibit decreased INa
due to reduced Na􏰃 channel expression and altered
gating.
♦ Moreover, Na􏰃 channel blocking drugs increase the
risk for sudden death in patients with ischemic heart
disease, possibly by facilitating the initiation of
reentrant excitation waves.
♦ Finally, INaL increases during myocardial ischemia,
explaining why INaL inhibition may be an effective
therapy for chronic stable angina.

56. TRANSIENT OUTWARD K+ CURRENT
(Ito)
♦supports early repolarization during phase 1.
♦The transient nature of Ito is secondary to its fast
activation and inactivation upon depolarization.

57. Nerbonne et al . Circ Res. 2001;89:944-956
Molecular composition of the cardiac K-ionchannels
Selectivity filter

58. Inherited diseases
♦ To date, only mutations in KCNE3 are linked to inherited
arrhythmia.
♦ An KCNE3 mutation was found in five related patients with
Brugada syndrome.
♦ expressed with Kv4.3, the mutation increased Ito,fast. It was
speculated that increased Ito,fast induces ST-segment elevation
in Brugada syndrome by aggravating transmural voltage
gradients.
♦ Another KCNE3 mutation was identified in one patient with
familial AF.postulated to cause AF by shortening AP duration
and facilitating atrial reentrant excitation waves.
♦ Recently, a genome-wide haplotype-sharing study associated a
haplotype on chromosome 7, harboring DPP6, with idiopathic
ventricular fibrillation in three distantly related families.

59. Acquired diseases
♦ Ito is reduced in AF, myocardial infarction, and heart failure.
♦ In myocardial infarction, Ito is down-regulated by the increased
activity of calcineurin, a phosphatase that regulates gene
transcription by dephosphorylating transcription factors.
♦ Sustained tachycardia in heart failure reduces Ito, probably
through a similar mechanism. However, Ito may be increased in
the hypertrophic phase preceding heart failure.
♦ Accordingly, Kv4.3 mRNA and protein levels decrease during
progression of hypertrophy to heart failure.
♦ Finally, Ito may be reduced and contribute to QT interval
prolongation in diabetes.
♦ Importantly, with certain delay, insulin therapy partially restores
Ito, maybe by enhancing Kv4.3 expression.

60. Cardiac Ca2􏰑 + current (I ) &
intracellular Ca2􏰑 +transients
♦ The L-type (long-lasting) inward Ca2􏰑 current (ICa,L) is largely
responsible for the AP plateau.
♦ Ca2+􏰑 influx by ICa,L activates Ca2+􏰑 release channels (ryanodine
receptor [RyR2]), located in the sarcoplasmic reticulum membrane.
♦ Sarcoplasmic reticulum Ca2􏰑+ release (Ca2􏰑 transients) via RyR2
channels couples excitation to contraction in myocytes.
♦ Beside ICa,L, T-type (tiny) Ca2􏰑 current (ICa,T) is identified in SAN
and AVN myocytes.
♦ ICa,T is believed to contribute to AP formation in pacemaker cells.

61. Inherited diseases
CACNA1C mutations
Timothy syndrome (LQTS type 8)
♦ cardiac manifestations of TS include
1. fetal bradycardia and extreme prolongation of the QT
interval (QTc >500 msec), often with macroscopic T wave
alternans and a 2 : 1 atrioventricular (AV) block at birth.
2. abnormalities frequently coincide with congenital heart
defects or cardiomyopathies.
3. The extracardiac abnormalities often consist of simple
syndactyly (webbing of the toes and fingers), dysmorphic
facial features, abnormal dentition, immune deficiency,
severe hypoglycemia, and developmental delay (including
autism).
♦ In Timothy syndrome, CACNA1C mutations delay
repolarization by increasing ICa,L

62. Acquired diseases
♦ Abnormalities in Ca2􏰑+ currents and/or intracellular Ca2+􏰑
transients in acquired diseases may induce both arrhythmia and
contractile dysfunction.
♦ In AF, Cav1.2 mRNA and protein levels are down-regulated,
resulting in ICa,L reduction, which contributes to AP
shortening
♦ In heart failure, Cav1.2 expression is reduced but ICa,L density
remains unchanged due to increased phosphorylation and,
consequently earlier activation, of Ca2􏰑 channels.
♦ Despite unchanged ICa,L, sarcoplasmic reticulum Ca2􏰑
transients are smaller and slower in heart failure, causing
contractile dysfunction
♦ In myocardial infarction, ICa,L is reduced in the border zone of
the infarcted area.
♦ Additionally, acute ischemia inhibits ICa,L via extracellular
acidosis and intra- cellular Ca2􏰑 and Mg2􏰑 accumulation.

63. Ultra-rapidly activating delayed
outward rectifying current (IKur)
♦ Kv1.5 is mainly expressed in the atria,
♦ IKur is detected only in atrial myocytes.
♦ Thus, IKur plays a role in atrial repolarization.
♦ activates rapidly upon depolarization but displays
very slow inactivation.

64. Inherited diseases
familial AF(mutation –loss of function KCNA5)
/Missense
♦ cause AF through AP prolongation and EAD
occurrence.
♦ KCNA5 missense mutations were found in two
patients with long QT intervals and cardiac arrest.
♦ Because both of these mutations did not change
Kv1.5 expression and/or channel gating and
because IKur is detected only in the atria, the
contribution of KCNA5 mutations to ventricular
arrhythmogenesis remains controversia

65. Acquired diseases
♦ IKur may be affected in myocardial ischemia.
♦ Decreased Kv levels were reported for the
epicardial border zone of infarcted hearts and
ischemic damage disrupted the normal location of
Kv1.5 in the intercalated disks.15

Whereas IKur defects may be arrhythmogenic in
ischemia, IKur block may act therapeutically in AF.
♦ Because IKur is atrium-specific, a drug specifically
targeting Kv1.5 channels could terminate AF by
preventing reentry through atrial AP prolongation.

66. ♦ However, because Kv1.5 mRNA and protein levels
are down-regulated in AF, the beneficial effect of
IKur block becomes less certain.
♦ Furthermore, because Kv1.5 is also expressed in
other organs (e.g., brain), discovery of drugs that
selectively inhibit atrial Kv1.5 chan- nels remains
necessary.

67. Rapidly activating delayed
outward rectifying current (IKr)
♦ KCNH2, also called the human-ether-a-go-go-related gene (hERG),
♦ Belying its name, IKr activation upon depolarization is not rapid, but
inactivation thereafter is very fast, resulting in a small outward K􏰑
current near the end of the AP upstroke.
♦ However, during early repolarization, the channel rapidly recovers from
inactivation to produce large IKr amplitudes during AP phases 2 and 3.
♦ Next, the channel deactivates (closes) slowly (in contrast to inactivation,
deactivation is a voltage-independent process).
♦ Under normal conditions, IKr is largely responsible for repolarization of
most cardiac cells.
♦ Interaction of Kv11.1 with its 􏰑beta-sub- unit MiRP1 (encoded by
KCNE2) induces earlier activation and accelerates deactivation.

68. Inherited diseases
LQT2/LQT6
KCNH2/KCNE2 loss-of-function mutations
♦ LQTS type 2, -caused by KCNH2 loss-of-function mutations
♦ This translates into AP and QT interval prolongation and may
generate EADs to trigger torsades de pointes.
♦ KCNH2 mutations reduce IKr, mostly by impairing the trafficking
of Kv11.1 proteins to the sarcolemma
♦ mutations in KCNE2 also reduce IKr and cause the less prevalent
LQTS type 6.

69. Short QT syndrome
gain-of-function mutation in KCNH2
♦ rare disease
♦ associated with short QT intervals
♦ increased risk for AF and VF.
♦ resulting IKr increase achieved by altered gating hastens
repolarization, thereby shortening AP duration and
facilitating reentrant excitation waves to induce atrial
and/or ventricular arrhythmia.
♦ Accordingly, gain-of-function mutations in KCNE2 have
been found in two families with AF.

70. Acquired diseases
♦ IKr may not be changed in AF or heart failure.
♦ In MI, Kv11.1 mRNA levels and IKr are reduced, and AP duration
is prolonged
♦ Conversely, during acute ischemia, IKr is increased and APD is
shortened. Such changes may be arrhythmogenic during ischemia.
♦ In diabetes, IKr reduction contributes to QT interval prolongation.
Accordingly,Kv11.1 levels are down-regulated; this may be due to
reduced protein synthesis, as KCNH2 mRNA levels are normal.
♦ Importantly, hyperglycemia depresses IKr, whereas insulin therapy
prevents or restores IKr function and shortens QT intervals.
♦ Finally, by blocking IKr, a large variety of drugs prolong QT
interval and increase the risk for TDP

71. Slowly activating delayed outward
rectifying current (IKs)
♦ only co-expression of KCNQ1 with minK-encoding KCNE1
yields currents that resemble IKs: a K􏰑 current that
activates slowly upon depolarization, displays no
inactivation, and deactivates slowly during repolarization.
♦ IKs is markedly enhanced by 􏰑beta-adrenergic stimulation
through channel phosphorylation by protein kinase A
(requiring A-kinase anchoring proteins [AKAPs]) and
protein kinase C (requiring minK). This implies that IKs
contributes to repolarization, especially when beta 􏰑-
adrenergic stimulation is present.

72. Inherited diseases IKs
LQT1 loss-of-function mutations in KCNQ1/
LQT5 loss-of-function mutations in KCNE1/
LQTS type 11mutation in AKAP9
♦ prolonged AP durations and QT intervals.
♦ Arrhythmia usually occurs during exercise or
emotional stress, probably because mutant IKs
does not increase sufficiently during 􏰋 beta 􏰑-
adrenergic stimulation.
♦ Accordingly, 􏰑􏰋 beta -adrenergic blocking drugs
suppress arrhythmic events in LQT1.

73. ♦ Loss-of-function mutations in both alleles of KCNQ1 or
KCNE1 cause the very rare Jervell and Lange-Nielsen
syndrome (JLNS) type 1 or 2, respectively. JLNS
encompasses 1% to 7% of all genotyped LQTS patients
and is characterized by, in addition to QT interval
prolongation, arrhythmia and congenital deafness, the
latter due to deficient endolymph secretion.
♦ KCNQ1 gain-of-function mutations are anecdotally linked
to short QT syndrome (type 2)
♦ Moreover, an KCNQ1 gain- of-function mutation is
reported to cause familial AF by shortening atrial AP
duration and facilitating reentry.

74. Inward rectifying current (IK1)
♦ IK1 stabilizes the resting membrane potential of atrial
and ventricular myocytes during phase 4 and
contributes to the terminal portion of phase 3
repolarization
♦ IK1 channels are closed during AP phases 1 and 2.
♦ Voltage- dependent block by intracellular Mg2􏰑
underlies channel closing, while unblocking enables
channel opening
♦ IK1 is almost absent in SAN and AVN myocytes

75. Inherited diseases
Loss-of-function mutations in KCNJ2
♦ linked to Andersen- Tawil syndrome, a rare disease characterized by Triad of
clinical findings, including periodic paralysis, dysmorphic features, and
ventricular arrhythmias
♦ ECG abnormalities in ATS may include pronounced QTU prolongation,
prominent U waves, and ventricular ectopy, including polymorphic ventricular
tachycardia (VT), bigeminy, and bidirectional VT.
♦ KNCJ2 mutations reduce IK1 by encoding defective Kir2.1 subunits, which
generate nonfunctional channels and/or bind to normal subunits to disrupt their
function (“dominant-negative effect”). IK1 reduction may trigger arrhythmia by
allowing inward currents, which are no longer counterbalanced by the strong
outward IK1, to gradually depolarize the membrane potential during phase 4.
♦ Membrane depolarization during phase 4 induces arrhythmia by facilitating
spontaneous excitability.
♦ Alternatively, IK1 reduction may trigger arrhythmia by prolonging AP duration
and triggering EADs.

76. Facial and
skeletal
features in
Andersen-
Tawil
syndrome

77. Acquired diseases IK1
♦ In chronic AF, IK1 is increased and Kir2.1 mRNA and
protein levels are elevated.
♦ Increased IK1 corresponds to more negative resting
potentials and, together with reduced ICa,L, accounts for
AP shortening in AF.
♦ Reduced IK1 densities are measured in myocytes of
animal hearts postinfarction. Moreover, various factors
during ischemia (e.g., intracellular Ca2􏰑, Mg2􏰑, and/or
Na􏰑 accumulation, and acidosis) may inhibit IK1.2
♦ IK1 reduction in heart failure or ischemia may facilitate
spontaneous excitability and trigger arrhythmia.

78. Pacemaker current (If)
♦ The pacemaker current enables spontaneous initiation of cardiac
electrical activity.
♦ funny current (If) :because it displays unusual gating properties.
♦ If is a mixed Na􏰑/K􏰑 current, which activates slowly upon
hyperpolarization and inactivates slowly in a voltage-independent
manner (deactivation) upon depolarization
♦ If conducts an inward current during phases 3 and 4 and may underlie
slow membrane depolarization in cells with pacemaker activity (i.e.,
cells with If and little or no IK1).
♦ If activation is accelerated when intracellular cyclic adenosine
monophos- phate (cAMP) levels are increased. Thus, If mediates heart
rate regulation by sympathetic and parasympathetic activity, which
control synthesis and degradation of intracellular cAMP, respectively.
♦ Accordingly, channels responsible for If are named hyperpolarization-
activated cyclic nucleotide-gated (HCN) channels.
♦ Four 􏰑-subunit isoforms are described (HCN1-4, encoded by HCN1-
4), which are preferentially expressed in SAN and AVN myocytes, and
Purkinje fibers

79. Inherited diseases
♦ Heterozygous HCN4 mutations were found in
individuals with mild to severe sinus bradycardia.
♦ Heterologous expression revealed that these
mutations decrease HCN channel expression,
decelerate If activation, or, when located in cyclic
nucleotide-binding domains (CNBDs) abolish
sensitivity of HCN channels to cAMP.
♦ These effects imply that HCN4 mutations cause
bradycardia by reducing If and the speed of
membrane depolarization during phase 4; this results
in slower pacemaking rates in SAN myocytes.

80. Acquired diseases
♦ Increased HCN expression in atrial or ventricular myocytes in pathologic
conditions could initiate arrhythmia by triggering spontaneous excitation of
nonpacemaker myocytes.
♦ Indeed, increased HCN2/HCN4 mRNA and protein levels are found in atria of
patients with AF and in ventricular tissues of heart failure patients.
♦ Accordingly, larger If amplitudes were recorded in myocytes that were
obtained from failing hearts.
♦ If recently has become a target for pharmacologic studies aimed at discovering
drugs to decrease heart rates in patients with ischemic heart disease.
♦ Elevated heart rates in these patients are associated with increased risk for
mortality. Whereas current heart rate lowering drugs adversely affect cardiac
contractility, selective If inhibition is is believed to lower heart rate without
impairing cardiac contractility
♦ To date ivabradine is the only If blocker registered

81. Ion channelopathies:
♦ Long QT syndrome
♦ Brugada syndrome
♦ Short QT syndrome
♦ Catecholaminergic
Polymorphic
Ventricular
Tachycardia
♦ Familial WPW
♦ Familial AF
♦ PCCD (Lenégrés
disease)
♦ Congenital SSS

82. Congenital Long QT syndrome:
♦ Prevalence is 1 in 5000
♦ Untreated 50% pts will die by 10 yrs
♦ Characterized by prolonged QTc (>440msec in males,
>450 msecs in females), recurrent syncope, TDP, SCD
♦ Prolonged QTc is due to prolonged APD
– Reduced K efflux (loss of function mutation,
Ikr,Iks,Ik1)
– Increased Na influx (gain of function mutation)
♦ Autosomal dominant & recessive types
♦ >470 allelic mutations

83. Mutations:

84. Mechanism of arrythmia
♦ Prolongation of AP leads to EAD
♦ Heterogeneity of AP – reentrant excitation

85. Genotype-phenotype correlation:
trigger for cardiac event
0
10
20
30
40
50
60
70
LQT1 LQT2 LQT3
EXERCI SE
EMOTI ON
SLEEP,REST
OTHER
Circulation 2001;103;89-95

87. Genotype-phenotype correlation
LQT1 LQT2 LQT3
Silent
carrier rate
36% 19% 10%
Influence
of sex
None Females males
symptoms More
asymptomatic
More
symptomatic
More lethal

88. Diagnosis of Long QT syndrome:
Schwartz score
♦ 1 point: low probability,
♦ 2-3 points: intermediate
probability;
♦ ≥4 points: high probability
(definite LQTS)

89. Sensitivity and specificity of
different diagnostic modalities:
Sensitivity specificity
QTc 74.0%[62–90] 90.3%[84–100]
Clinical score 67%[48–94] 100%
Genetic test 96.5%[95–98] 98.5%[97–100%]
Genet Med 2006:8(3):143–155.

90. Risk Stratification among Patients
with the Long-QT Syndrome
♦ QTc is the strongest
predictor(>500 msecs
highest risk)
♦ Aborted SCD have
a RR of 12.9
♦ JLN & LQTS with
syndactyly
♦ Immediate post partum
JACC Vol. 48, (5), 2006; e247–e346
NEJM 2003;348:1866-74.

91. Treatment:
♦ Avoid competitive sports & LQT2 avoid
acoustic stimuli
♦ Avoid QT prolonging drugs
♦ Beta-blockers for all patients
♦ K supplementation may be beneficial in
LQT2
♦ Mexiletine has been useful in LQT3
♦ ICD for cardiac arrest & those with syncope
/VT on beta-blockers

92. Genotype and ß- blocker therapy
Circulation 2001;103;89-95

93. Short QT syndrome
♦ Rare disorder (only 6 families with 23 pts
reported)
♦ Reported first in 2000 by Gussak et al
♦ Presentation across wide age range from
neonate to elderly
♦ Atrial fibrillation, syncope /& Family h/o
SCD

94. ECG: short QTc<300 ms, short/absent
ST seg, tall narrow T wave

95. Short QT syndrome: (contd.)
♦ Inducible VF in 90% at EPS, high incidence
of SCD
♦ High incidence of AF (70%)

96. SQT1 HERG (IKr)
SQT2 KvLQT1 (IKs)
SQT3 KCNJ2 (IK1)
GENE MUTATIONS: GAIN OF FUNCTION

97. ♦ Surface ECG
– T symmetric in SQT1 but asymmetric in SQT
– SQT2- inverted T waves can be observed.
– SQT5- BrS–like ST elevation in the right precordial lead

98. Treatment:
♦ Robust genotype–phenotype correlation
data are not yet available
♦ But quinidine has been shown to normalize
QT in SQT1 & recommended for this group
♦ ICD is the treatment of choice for those
with syncope/aborted SCD/family h/o SCD
♦ High incidence of inappropriate shocks due
to short coupled tall T waves

99. CPVT
♦ First described in 1975 by Reed
♦ Rare disorder with both autosomal dominant &
recessive forms, family history in 30%
♦ Predominantly affects children and adolescents
♦ Present with syncope, seizures or SCD
♦ Typically have bidirectional or polymorphic VT in
response to adrenergic stimuli (exercise/emotional
stress)
♦ Initiated by DAD

101. DA
D

102. Management
♦ Risk stratification is based
entirely on clinical
considerations.
♦ Regular follow-up visits, TMT
constitute an effective approach
for β blocker dose titration and
arrhythmia monitoring
♦ Mainstay of Management β
Blockers [long term follow up
40% have symptom recurrence]
♦ ICD in β blocker ineffective
cases or survivor of Cardiac
arrest

103. Familial AF
♦ 30 % of pts with AF, with/without structural
heart disease, have a positive family history
♦ 7 genes have been identified as of now
– all encode for subunits of K channels
– All mutations confer a gain-of-function
– All mutations shorten the atrial AP duration and
the atrial effective refractory period

104. Mutations in AF:

105. ♦ PCCD (Lenégrés disease)
– In some cases associated with loss of function mutation
in SCNA5 (autosomal dominant)
– Loss of NA channel function leads to slow rise in AP,
reduced depolarization current & slow conduction
♦ Congenital SSS- 2 mutations described
– HCN4 gene in 2 cases; HCN4 encodes If, a pacemaker
channel resp. for slow diastolic depolarization in
pacemaker cells
– 3 families, SCNA5 mutation, mechanism unclear

106. Genetic testing:
♦ Genetic testing usually available via IRB-protocol for
research purpose- turnaround time 6-24 mths
♦ For CPVT (70%), LQT 7/anderson ds (70%) studies still
done by research protocol
♦ May 2004-first commercial genetic test was released by
Genaissance Pharmaceuticals (FAMILION)
♦ This tests for 5 ion channel genes-
– K channel KCNQ1, KCNE1, KCNE2, KCNH2 (LQT 1,2,5,6;
short QT 1,2),
– SCNA5 (LQT 3, BrS, PCCD, congenital SSS)
♦ Results available in 4 weeks, sampling error <1%

107. Indications:
♦ All patients with clinical diagnosis of
channelopathy and their first degree relatives
♦ Unexplained exertional syncope, drug induced
TDP
♦ Benefits
– Establish a diagnosis in borderline cases
– Screen asymptomatic relatives
– Tailor therapy as per phenotype in case of long QT
– Genetic counselling
– Research purpose

108. limitations:
♦ 25% cases of long QT syndrome with a strong
clinical probability
♦ Only 20% cases of BrS have SCNA5 mutation
♦ Most families have private mutations that may be
missed,
– study from mayo clinic with the FAMILION test
diagnosed new mutations in 40% of positive pts (Heart
Rhythm 2005;2:507–517)
♦ Channelopathies follow menedelian genetics with
incomplete penetrance and variable expression
♦ Ethical issues
♦ Cost 5400$/ screening test and 900$ for family
specific confirmatory test

109. Conclusions
• Ion channel disease offers a paradigm for the
understanding of a molecular lesion in the patient
and its translation to phenotype and eventually
management decisions.
• Nonetheless there are many gaps in our
understanding, particularly of incomplete
penetrance, risk stratification and the underlying
pathophysiology of some of the conditions.
• Still, progress is rapid, and patients and their
families will continue to benefit as our knowledge
and understanding improves.