ArticlePDF AvailableLiterature Review

Modernized Classification of Cardiac Antiarrhythmic Drugs

October 2018
Circulation 138(17):1879-1896

October 2018
138(17):1879-1896

DOI:10.1161/CIRCULATIONAHA.118.035455

Authors:

Ming Lei

University of Oxford

Christopher L-H Huang

University of Cambridge

Background: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. Methods: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. Results: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. Conclusions: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

Surface and intracellular membrane ion channels, ion exchangers, transporters, and ionic pumps involved in cardiomyocyte electrophysiological excitation and activation. A, Their grouping by pharmacological targets listed in Table 1. B through E, Activation and inactivation of ion channels, currents, underlying proteins, and encoding genes and their contributions to (B) inward depolarizing and (C) outward repolarizing currents bringing about cardiac action potentials (APs). Ventricular (D) and atrial (E) APs comprise rapid depolarizing (phase 0), early repolarizing (phase 1), brief (atrial) or prolonged (ventricular) phase 2 plateaus (phase 2), phase 3 repolarization, and phase 4 electric diastole. In these, inward Na + or Ca 2+ currents drive phase 0 depolarization and Ca 2+ current maintains the phase 2 plateau (B), and a range of outward K + currents (C) drive phase 1 and phase 3 repolarization. Phase 4 resting potential restoration is accompanied by a refractory period required for Na + channel recovery. The resulting wave of electric activity and refractoriness is propagated through successive sino-atrial node, atrial, atrioventricular, Purkinje, and endocardial and epicardial ventricular cardiomyocytes. CaMKII indicates calcium/calmodulin kinase II; Cx, connexin; G i , inhibitory G protein; G s , stimulatory G-protein; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; Nav1.5, cardiac Na + channel protein; PKA, protein kinase A; RyR2, cardiac ryanodine receptor type 2; and TRP, transient receptor potential channel. Adapted from Huang 19 with permission. Copyright (c) 2017, American Physiological Society.

…

Relationships between biophysical actions of Class I drugs on cardiac Na + channel protein (Nav1.5) and their consequent electrophysiological antiarrhythmic and proarrhythmic effects. A, Initial depolarization activates the Nav1.5 voltage sensor, in turn causing a transition from its resting, closed, to its open state, permitting extracellular Na + influx through the selectivity filter of the channel. The resulting regenerative depolarization results in slower transitions into an inactivated state, causing channel closure, from which recovery to the resting state requires membrane potential repolarization. The different Class Ia through Id drugs act at different stages in this reaction cycle and on differing early, I Na , and late, I NaL , Na + current components. This results in (B) differential actions on action potential (AP) conduction, triggering, and duration, with proarrhythmic or antiarrhythmic effects, depending on the background clinical conditions. BrS indicates Brugada syndrome; DAD, delayed afterdepolarization; EAD, early afterdepolarization; and LQTS, long-QT syndrome.

…

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Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 October 23, 2018 1879

Key Words: anti-arrhythmia agents

◼ arrhythmias, cardiac ◼ homeostasis

◼ ion channels

BACKGROUND: Among his major cardiac electrophysiological

contributions, Miles Vaughan Williams (1918–2016) provided a classiﬁcation

of antiarrhythmic drugs that remains central to their clinical use.

METHODS: We survey implications of subsequent discoveries concerning

sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules,

developing an expanded but pragmatic classiﬁcation that encompasses

approved and potential antiarrhythmic drugs on this centenary of his

birth.

RESULTS: We ﬁrst consider the range of pharmacological targets,

tracking these through to cellular electrophysiological effects. We retain

the original Vaughan Williams Classes I through IV but subcategorize

these divisions in light of more recent developments, including the

existence of Na+ current components (for Class I), advances in autonomic

(often G protein–mediated) signaling (for Class II), K+ channel subspecies

(for Class III), and novel molecular targets related to Ca2+ homeostasis (for

Class IV). We introduce new classes based on additional targets, including

channels involved in automaticity, mechanically sensitive ion channels,

connexins controlling electrotonic cell coupling, and molecules underlying

longer-term signaling processes affecting structural remodeling. Inclusion

of this widened range of targets and their physiological sequelae provides

a framework for a modernized classiﬁcation of established antiarrhythmic

drugs based on their pharmacological targets. The revised classiﬁcation

allows for the existence of multiple drug targets/actions and for adverse,

sometimes actually proarrhythmic, effects. The new scheme also aids

classiﬁcation of novel drugs under investigation.

CONCLUSIONS: We emerge with a modernized classiﬁcation preserving

the simplicity of the original Vaughan Williams framework while aiding

our understanding and clinical management of cardiac arrhythmic events

and facilitating future developments in this area.

SYSTEMATIC REVIEW

Modernized Classiﬁcation of Cardiac

Antiarrhythmic Drugs

published on behalf of the American

Heart Association, Inc., by Wolters

Kluwer Health, Inc. This is an open

access article under the terms of the

Creative Commons Attribution License,

which permits use, distribution, and

reproduction in any medium, provided

that the original work is properly cited.

Ming Lei, BM, MSc, DPhil

Lin Wu, BM, MSc, MD

Derek A. Terrar, BSc, MA,

PhD

Christopher L.-H. Huang,

MA, BMBCh, DM, DSc,

PhD, MD, ScD

https://www.ahajournals.org/journal/circ

Circulation

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

October 23, 2018 Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455

1880

STATE OF THE ART

The year 2018 marks the centenary of the birth

of Miles Vaughan Williams and provides an op-

portunity to revisit his electrophysiological and

pharmacological contributions concerning cardiac ar-

rhythmias. The classic work deﬁned 4 major possible

modes of action of antiarrhythmic drugs variously

modifying Na+, K+, and Ca2+ channel function and in-

tracellular mechanisms regulated by adrenergic activ-

ity. These insights provided the scientiﬁc basis for a

landmark classiﬁcation of antiarrhythmic drugs based

on the actions of these drugs on cardiac action poten-

tial (AP) components and their relationship to arrhyth-

mias.1,2 This classiﬁcation proved, and remains, central

to clinical management. Thus, Class I drugs produce

moderate (Ia), weak (Ib), or marked (Ic) Na+ channel

block and reduce AP phase 0 slope and overshoot

while increasing, reducing, or conserving AP duration

(APD) and effective refractory period (ERP), respective-

ly.3 Class II drugs, comprising β-adrenergic inhibitors,

reduce sino-atrial node (SAN) pacing rates and slow

atrioventricular node (AVN) AP conduction.4 Vaughan

Williams’s pioneering studies of β-adrenergic inhibi-

tors remain a mainstay of antiarrhythmic therapy.5

Class III drugs, comprising K+ channel blockers, delay

AP phase 3 repolarization and lengthen ERP. Finally,

Class IV drugs, comprising Ca2+ channel blockers, re-

duce heart rate and conduction, acting particularly on

the SAN and AVN.2

APPROACHES TO DEVELOPMENTS

OF NEW DRUG CLASSIFICATION

SCHEMES: THE SICILIAN GAMBIT

A review article published simultaneously in European

Heart Journal and Circulation in 1991 represents an im-

portant step in the integration of these developments

into guidelines for antiarrhythmic drug therapy.6 The

meeting in Taormina, Sicily, sought to furnish open-

ing moves toward new classiﬁcations of antiarrhythmic

drug therapy, akin to the Queen’s Gambit represent-

ing a particularly aggressive option in chess, and this

new approach was called the Sicilian Gambit. This more

complete and ﬂexible framework adopted a pathophys-

iological foundation identifying vulnerable parameters

reﬂecting electrophysiological properties or events with

pharmacological modiﬁcations that would terminate or

suppress the arrhythmia with minimal undesirable car-

diac effects.7–9 It correlated information on molecular

targets, cellular mechanisms, functional targets, and

clinical arrhythmias for individual drugs with similari-

ties and differences in their effects, accommodating

their multiple actions. Although not then seeking a

completed formal classiﬁcation system, it furnished an

accurate and comprehensive updated analysis of anti-

arrhythmic drugs. Although this analysis increased our

understanding of drug action, the revised approach has

not won widespread acceptance by clinicians and edu-

cators, possibly owing to its inevitable complexity. The

Sicilian Gambit requires detailed knowledge of cellular

and molecular targets of drugs under consideration.

This may have made it intimidating or impractical for

regular clinical use.

MODERNIZED SCHEME BASED ON THE

VAUGHAN WILLIAMS APPROACH

The Vaughan Williams scheme, for all its limitations in

light of subsequent developments in the cardiac elec-

trophysiological ﬁeld, thus remains the most useful,

clinically and pedagogically popular approach to cat-

egorizing antiarrhythmic drugs. Table 1 summarizes a

pragmatic development and expansion of that original

classiﬁcation encompassing principal actions of both

current and potential antiarrhythmic agents, retaining

the original Classes I through IV as its central core (Ta-

ble I in the online-only Data Supplement). We thereby

address interests and requirements of current workers

in the ﬁeld, mainly citing major reviews rather than

original research articles, emphasizing broad principles

and generalizations. We ﬁrst identify major pharmaco-

logical targets, whether speciﬁc membrane ion chan-

nels, transporters, cytosolic biomolecules, or regulators

(Figure1A) strategic to cardiac electrophysiological ac-

tivity (Figure1B). Most therapeutic agents either block

Clinical Perspective

What Is New?

• We develop a modernized comprehensive clas-

siﬁcation of both established and potential antiar-

rhythmic drugs that preserves the basic simplicity

of the widely accepted classic Vaughan Williams

framework.

• This incorporates advances in our understanding

made over the past half-century, covering all the

major currently known classes of antiarrhythmic

mechanisms

What Are the Clinical Implications?

• It will provide a valuable guide to our basic under-

standing of the principal and subsidiary categories

of antiarrhythmic and proarrhythmic drug actions

in terms of their electrophysiological actions on

speciﬁc currently known and potential targets

bearing on cardiac excitation.

• It will facilitate therapeutic decisions in current clin-

ical practice and aid in the development of future

novel antiarrhythmic drugs.

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 October 23, 2018 1881

STATE OF THE ART

Table 1. An Updated Classiﬁcation of Current Antiarrhythmic Pharmacological Drugs

Class Subclass

Pharmacological

Targets Electrophysiological Effects

Examples of

Drugs

Major Clinical

Applications

Corresponding

Likely Therapeutic

Mechanism(s)

HCN channel blockers

0 HCN channel–

mediated

pacemaker current

(If) block

Inhibition of If reducing

SAN phase 4 pacemaker

depolarization rate, thereby

reducing heart rate; possible

decreased AVN and Purkinje

cell automaticity; increase in RR

intervals10–14

Ivabradine Stable angina and chronic

heart failure with heart

rate ≥70 bpm

Potential new applications

for tachyarrhythmias15

Reduction in SAN

automaticity

Voltage-gated Na+ channel blockers

I Ia Nav1.5 open

state; intermediate

(τ≈1–10 seconds)

dissociation

kinetics; often

concomitant K+

channel block

Reduction in peak INa, AP

generation, and (dV/dt)max

with increased excitation

threshold; slowing of AP

conduction in atria, ventricles,

and specialized ventricular

conduction pathways;

concomitant IK block increasing

APD and ERP; increase in QT

intervals16–23

Quinidine,

ajmaline,

disopyramide

Supraventricular

tachyarrhythmias,

particularly recurrent atrial

ﬁbrillation; ventricular

tachycardia, ventricular

ﬁbrillation (including SQTS

and Brugada syndrome)24–27

Reduction in ectopic

ventricular/atrial

automaticity

Reduction in

accessory pathway

conduction

Increase in

refractory period,

decreasing reentrant

tendency16,28,29

Ib Nav1.5 open state;

rapid dissociation

(τ≈0.1–1 second);

INa; window current

Reduction in peak INa, AP

generation and (dV/dt)max

with increased excitation

threshold; slowing of

AP conduction in atria,

ventricles, and specialized

ventricular conduction

pathways; shortening of

APD and ERP in normal

ventricular and Purkinje

myocytes; prolongation of

ERP and postrepolarization

refractoriness with reduced

window current in ischemic,

partially depolarized cells

Relatively little

electrocardiographic effect;

slight QTc shortening16–23,30

Lidocaine,

mexiletine

Ventricular

tachyarrhythmias

(ventricular tachycardia,

ventricular ﬁbrillation),

particularly after

myocardial infarction24,26

Reduction in

ectopic ventricular

automaticity

Reduction in DAD-

induced triggered

activity

Reduced reentrant

tendency by

converting

unidirectional to

bidirectional block,

particularly in

ischemic, partially

depolarized

myocardium16,28,29

Ic Nav1.5 inactivated

state; slow

dissociation (τ>10

seconds)

Reduction in peak INa, AP

generation and (dV/dt)max

with increased excitation

threshold; slowing of AP

conduction in atria, ventricles,

and specialized ventricular

conduction pathways;

reduced overall excitability;

prolongation of APD at high

heart rates; increase in QRS

duration16–23,30,31

Propafenone,

ﬂecainide

Supraventricular

tachyarrhythmias (atrial

tachycardia, atrial ﬂutter,

atrial ﬁbrillation, and

tachycardias involving

accessory pathways)

Ventricular

tachyarrhythmias resistant

to other treatment in

the absence of structural

heart disease, premature

ventricular contraction,

catecholaminergic

polymorphic ventricular

tachycardia24–27

Reduction in ectopic

ventricular/atrial

automaticity

Reduction in DAD-

induced triggered

activity

Reduced reentrant

tendency by

converting

unidirectional to

bidirectional block

Slowed conduction

and reduced

of excitability

particularly at rapid

heart rates blocking

reentrant pathways

showing depressed

conduction16,28,29

Id Nav1.5 late current Reduction in late Na+ current

(INaL), affecting AP recovery,

refractoriness, repolarization

reserve, and QT interval22,32

Ranolazine Stable angina, ventricular

tachycardia

As a potential new class of

drugs for the management

of tachyarrhythmias

Decrease in AP

recovery time

Reduction in EAD-

induced triggered

activity

(Continued )

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

October 23, 2018 Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455

1882

STATE OF THE ART

Autonomic inhibitors and activators

II IIa Nonselective

β- and selective

β1-adrenergic

receptor inhibitors

Inhibition of adrenergically

induced Gs protein-mediated

effects of increased adenylyl

kinase activity and [cAMP]i

with effects including slowed

SAN pacemaker rate caused

by reduced If and ICaL; increased

AVN conduction time and

refractoriness, and decreased

SAN pacing and triggered activity

resulting from reduced ICaL; and

reduced RyR2-mediated SR Ca2+

release and triggered activity;

increase in RR and PR intervals33

Nonselective

β inhibitors:

carvedilol,

propranolol,

nadolol. Selective

β1-adrenergic

receptor inhibitors:

atenolol, bisoprolol,

betaxolol,

celiprolol, esmolol,

metoprolol

Sinus tachycardia or other

types of tachycardic,

including supraventricular

(atrial ﬁbrillation, atrial

ﬂutter, atrial tachycardia),

arrhythmias

Rate control of atrial

ﬁbrillation and ventricular

tachyarrhythmias (ventricular

tachycardia, premature

ventricular contraction)

Note: atenolol,

propranolol, and nadolol

also used in LQTS; nadolol

used in catecholaminergic

polymorphic ventricular

tachycardia24–27

Reduction in SAN

automaticity

Reduction in AVN

automaticity

Reduction in ectopic

ventricular/atrial

automaticity

Reduction in EAD-/

DAD-induced

triggered activity

Reduced SAN reentry

Reduction in

AVN conduction

terminating

reentry5,16,29

IIb Nonselective

β-adrenergic

receptor activators

Activation of adrenergically

induced Gs-protein effects

of increasing adenylyl kinase

activity and [cAMP]i (see entry

above); decrease in RR and PR

intervals33

Isoproterenol Accelerating rates of

ventricular escape

rhythm in cases of

complete atrioventricular

block before deﬁnitive

pacemaker implantation

Acquired, often drug-related

bradycardia-dependent

torsades de pointes34

Increased escape

ventricular

automaticity

Suppression of

bradycardia-

dependent EAD-

related triggered

activity5,16,29

IIc Muscarinic M2

receptor inhibitors

Inhibition of supraventricular

(SAN, atrial, AVN) muscarinic

M2 cholinergic receptors (see

entry below); decreased RR and

PR intervals35–37

Atropine,

anisodamine,

hyoscine,

scopolamine

Mild or moderate

symptomatic sinus

bradycardia

Supra-His, AVN, conduction

block, eg, in vagal syncope

or acute inferior myocardial

infarction34

Increase in SAN

automaticity

Increase in AVN

conduction16,29

IId Muscarinic M2

receptor activators

Activation of supraventricular

(SAN, atrial, AVN) muscarinic M2

cholinergic receptors activates

KACh channels, hyperpolarizing

the SAN and shortening APDs

in atrial and AVN tissue, and

reduces [cAMP]i and therefore

ICaL and SAN If; inhibitory

effects on adenylyl cyclase and

cAMP activation, reducing its

stimulatory effects on ICaL, IKs, ICl,

and Iti in adrenergically activated

ventricular tissue; increased RR

and PR intervals35–37

Carbachol,

pilocarpine,

methacholine,

digoxin

Sinus tachycardia

or supraventricular

tachyarrhythmias24,27

Reduction in SAN

automaticity

Reduced SAN reentry

Reduction in

AVN conduction,

terminating

reentry16,29

IIe

Adenosine A1

receptor activators

Activation of adenosine A1

receptors in supraventricular

tissue (SAN, atrial, AVN) activates

G protein–coupled inward

rectifying K+ channels and

IKAdo current, hyperpolarizing

the SAN and shortening APDs

in atrial and AVN tissue, and

reduces [cAMP]i and therefore

ICaL and SAN If; inhibitory

effects on adenylyl cyclase and

cAMP activation, reducing its

stimulatory effects on ICaL, IKs, ICl,

and Iti in adrenergically activated

ventricular tissue; increased RR

and increased PR intervals38

Adenosine, ATP;

aminophylline acts

as an adenosine

receptor inhibitor

Acute termination of AVN

tachycardia and cAMP-

mediated triggered VTs

Differentiation of

sinus from atrial

tachycardia24,26,27,34

Reduction in SAN

automaticity

Reduction in

AVN conduction,

terminating reentry

Reduction in

EAD-/DAD-

induced triggered

activity16,29,39

Table 1. Continued

Class Subclass

Pharmacological

Targets Electrophysiological Effects

Examples of

Drugs

Major Clinical

Applications

Corresponding

Likely Therapeutic

Mechanism(s)

(Continued )

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 October 23, 2018 1883

STATE OF THE ART

K+ channel blockers and openers

III

Voltage

dependent

K+ channel

blockers

IIIa

Nonselective K+

channel blockers

Block of multiple K+ channel

targets resulting in prolonged

atrial, Purkinje, and/or

ventricular myocyte AP

recovery, increased ERP, and

reduced repolarization reserve;

prolonged QT intervals35,40,41

Ambasilide,

amiodarone,

dronedarone

Ventricular tachycardia

in patients without

structural heart disease or

with remote myocardial

infarction; tachyarrhythmias

with Wolff-Parkinson-White

syndrome

Atrial ﬁbrillation with

atrioventricular conduction

via accessory pathway

Ventricular ﬁbrillation

and premature ventricular

contraction

Tachyarrhythmias associated

with supraventricular

arrhythmias and atrial

ﬁbrillation24–27

Increase in AP

recovery time

Increase in refractory

period, with

decreased reentrant

tendency

Note: amiodarone

also slows sinus

node rate and

atrioventricular

conduction; see

Table216,29

Kv11.1 (HERG)

channel–mediated

rapid K+ current

(IKr) blockers

Prolonged atrial, Purkinje,

and ventricular myocyte AP

recovery, increased ERP, and

reduced repolarization reserve;

prolonged QT intervals41

Dofetilide,

ibutilide,

sotalol

Ventricular tachycardia in

patients without structural

heart disease or with remote

myocardial infarction

Tachyarrhythmias

associated with Wolff-

Parkinson-White

syndrome

Atrial ﬁbrillation

with atrioventricular

conduction via accessory

pathway, ventricular

ﬁbrillation, premature

ventricular contraction

Tachyarrhythmias

associated with

supraventricular

arrhythmias and atrial

ﬁbrillation24–27

Increase in AP

recovery time

Increase in refractory

period with

decreased reentrant

tendency16,29,42

Kv7.1 channel–

mediated, slow

K+ current (IKs)

blockers

Prolonged atrial, Purkinje,

and ventricular myocyte AP

recovery, increased ERP, and

reduced repolarization reserve;

prolonged QT intervals35,40,41,43

No clinically

approved drugs

in use

Increase in AP

recovery time

Increase in refractory

period with

decreased reentrant

tendency16,29

Kv1.5 channel–

mediated,

ultrarapid K+

current (IKur)

blockers

Prolonged atrial AP recovery,

increased ERP, and reduced

repolarization reserve35

Vernakalant Immediate conversion of

atrial ﬁbrillation

Atrium-speciﬁc

actions: increase in

AP recovery time and

increase in refractory

period with decreased

reentrant tendency29

KV1.4 and KV4.2

channel–mediated

transient outward

K+ current (Ito1)

blockers

Prolonged atrial, Purkinje,

and ventricular myocyte AP

recovery, increased ERP, and

reduced repolarization reserve,

particularly in subepicardial as

opposed to subendocardial

ventricular cardiomyocytes35,41

Blocker under

regulatory review

for the acute

conversion of

atrial ﬁbrillation:

tedisamil

Increase in AP

recovery time;

increase in refractory

period, with

decreased reentrant

tendency29

Metabolically

dependent

K+ channel

openers

IIIb Kir6.2 (IKATP)

openers

Opening of ATP-sensitive K+

channels (IKATP), shortening AP

recovery, refractoriness, and

repolarization reserve in all

cardiomyocytes apart from SAN

cells; shortened QT intervals35,44,45

Nicorandil,

pinacidil

Nicorandil: treatment of

stable angina (second line);

pinacidil: investigational

drug for the treatment of

hypertension

Potential decrease in

AP recovery time

Table 1. Continued

Class Subclass

Pharmacological

Targets Electrophysiological Effects

Examples of

Drugs

Major Clinical

Applications

Corresponding

Likely Therapeutic

Mechanism(s)

(Continued )

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

October 23, 2018 Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455

1884

STATE OF THE ART

Transmitter

dependent

K+ channel

blockers

IIIc GIRK1 and GIRK4

(IKACh) blockers

Inhibition of direct or Gi protein

βγ-subunit–mediated activation

of IKACh, particularly in SAN,

AVN, and atrial cells, prolonging

APD and ERP and decreasing

repolarization reserve35,46

Blocker under

regulatory review

for management

of atrial

ﬁbrillation:

BMS 914392

Reduction in SAN

automaticity47

Ca2+ handling modulators

Surface

membrane

Ca2+ channel

blockers

IVa Nonselective

surface membrane

Ca2+ channel

blockers

Block of Ca2+ current (ICa),

resulting in inhibition of SAN

pacing, inhibition of AVN

conduction, prolonged ERP,

increased AP recovery time,

increased refractory period,

diminished repolarization

reserve, and suppression of

intracellular Ca2+ signaling;

increased PR intervals48,49

Bepridil Angina pectoris

Potential management

of supraventricular

tachyarrhythmias24,27

Reduction in

AVN conduction,

terminating reentry

Reduction in EAD-/

DAD-induced

triggered activity5,16,29

Cav1.2 and Cav1.3

channel mediated

L-type Ca2+ current

(ICaL) blockers

Block of Ca2+ current (ICa),

resulting in inhibition of SAN

pacing, inhibition of AVN

conduction, prolonged ERP,

increased AP recovery time,

increased refractory period,

diminished repolarization

reserve, and suppression of

intracellular Ca2+ signaling;

increased PR intervals48–50

Phenylalkylamines

(eg, verapamil),

benzothiazepines

(eg, diltiazem)

Supraventricular

arrhythmias and ventricular

tachycardia without

structural heart disease

Rate control of atrial

ﬁbrillation24,26,27

Reduction in

AVN conduction,

terminating reentry

Reduction in EAD-/

DAD-induced

triggered activity5,16,29

Cav3.1 channel

mediated T-type

Ca2+ current (ICaT)

blockers

Inhibition of SAN pacing,

prolonged His-Purkinje phase

4 repolarization, absent from

ventricular cells49

No clinically

approved drugs

in use

Intracellular

Ca2+ channel

blockers

IVb SR RyR2-Ca2+

channel blockers

Reduced SR Ca2+ release:

reduced cytosolic and SR

[Ca2+]31,33,48,51–54

Flecainide,

propafenone

Catecholaminergic

polymorphic ventricular

tachycardia

Reduction in DAD-

induced triggered

activity5,16,29

IP3R-Ca2+ channel

blockers

Reduced atrial SR Ca2+ release;

reduced cytosolic and SR [Ca2+]48

No clinically

approved drugs

in use

Sarcoplasmic

reticular

Ca2+-ATPase

activators

IVc Sarcoplasmic

reticular Ca2+

pump activators

Increased Ca2+-ATPase activity,

increased SR [Ca2+]33,48,53

No clinically

approved drugs

in use

Reduction in DAD-

induced triggered

activity5,16,29

Surface

membrane

ion exchange

inhibitors

IVd Surface membrane

ion exchanger (eg,

SLC8A) inhibitors

Reduced Na+-Ca2+ exchange

reduces depolarization

associated with rises in

subsarcolemmal [Ca2+]48,53

No clinically

approved drugs

in use

Reduction in EAD-/

DAD-induced

triggered activity5,16,29

Phosphokinase

and

phosphorylase

inhibitors

IVe Increased/decreased

phosphorylation

levels of cytosolic

Ca2+ handling

proteins

Includes CaMKII modulators:

altered intracellular Ca2+

signaling37,44,50,55–57

No clinically

approved drugs

in use

Reduction in EAD-/

DAD-induced

triggered activity

Mechanosensitive channel blockers

V Transient receptor

potential channel

(TRPC3/TRPC6)

blockers

Intracellular Ca2+ signaling58 Blocker under

investigation: N-

(p-amylcinnamoyl)

anthranilic acid

Reduction in EAD-/

DAD-induced

triggered activity

Table 1. Continued

Class Subclass

Pharmacological

Targets Electrophysiological Effects

Examples of

Drugs

Major Clinical

Applications

Corresponding

Likely Therapeutic

Mechanism(s)

(Continued )

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STATE OF THE ART

or open speciﬁc ion channels or, in the case of par-

ticular signaling molecules and receptors, activate or

inhibit the relevant pathway. We then summarize the

corresponding principal electrophysiological effects of

target modiﬁcation, including actions progressively in-

vestigated at the level of single cells, particular cardiac

regions, or the entire heart.7–9 These are illustrated by

clinically used drugs, their clinical indications, and likely

therapeutic mechanisms of action, acknowledging their

additional, often multiple, actions (Table 2), selecting

these from the wide range of clinically approved avail-

able agents (Table II in the online-only Data Supple-

ment) and, in some cases, the numerous investigational

agents under development (Table III in the online-only

Data Supplement).

Our approach retains but modiﬁes Vaughan Williams

Class I, adding a Class Id to include actions on recently

reported late Na+ current (INaL) components, recogniz-

ing their importance in long-QT syndrome (LQTS) type 3

(LQTS3). Class II conserves the β-adrenergic inhibitors but

now captures subsequent advances in our understanding

of autonomic, often G protein–mediated, signaling. Class

III is expanded to take into account the large number of

subsequently discovered K+ channel species determining

APD and subsequent refractoriness. Class IV now encom-

passes recently demonstrated and characterized molecu-

Gap junction channel blockers

VI Cx (Cx40, Cx43,

Cx45) blockers

Reduced cell-cell coupling and

AP propagation; Cx40: atria,

AVN, ventricular conduction

system; Cx43: atria and

ventricles, distal conduction

system; Cx45: SAN, AVN,

conducting bundles18,59

Blocker under

investigation:

carbenoxolone

Reduction in

ventricular/atrial

conduction

Reduction in

accessory pathway

conduction

Reduction in AVN

conduction

Upstream target modulators

VII Angiotensin-

converting enzyme

inhibitors

Electrophysiological

and structural (ﬁbrotic,

hypertrophic, or inﬂammatory)

remodeling47,60,61

Captopril,

enalapril, delapril,

ramipril, quinapril,

perindopril,

lisinopril,

benazepril,

imidapril,

trandolapril,

cilazapril

Management of

hypertension, symptomatic

heart failure

Potential application

reducing arrhythmic

substrate15,25

Reduction of

structural and

electrophysiological

remodeling changes

that compromise

AP conduction and

increase reentrant

tendency

Angiotensin

receptor blockers

Electrophysiological

and structural (ﬁbrotic,

hypertrophic, or inﬂammatory)

remodeling47,60,61

Losartan,

candesartan,

eprosartan,

telmisartan,

irbesartan,

olmesartan,

valsartan,

saprisartan

Management of

hypertension, symptomatic

heart failure

Potential application

reducing arrhythmic

substrate15,25

Reduction of

structural and

electrophysiological

remodeling changes

that compromise

AP conduction and

increase reentrant

tendency

Omega-3 fatty

acids

Electrophysiological

and structural (ﬁbrotic,

hypertrophic, or inﬂammatory)

remodeling60

Omega-3

fatty acids:

eicosapentaenoic

acid,

docosahexaenoic

acid,

docosapentaenoic

acid

Post–myocardial infarct

reduction of risk of cardiac

death, myocardial infarct,

stroke, and abnormal

cardiac rhythms26

Reduction of

structural and

electrophysiological

remodeling changes

that compromise

AP conduction and

increase reentrant

tendency

Statins Electrophysiological

and structural (ﬁbrotic,

hypertrophic, or inﬂammatory)

remodeling60

Statins Post–myocardial infarct

reduction of risk of cardiac

death, myocardial infarct,

stroke, and abnormal

cardiac rhythms25

Reduction of

structural and

electrophysiological

remodeling changes

that compromise

AP conduction and

increase reentrant

tendency

AP indicates action potential; APD, action potential duration; AVN, atrioventricular node; CaMKII, calcium/calmodulin kinase II; DAD, delayed afterdepolarization;

EAD, early afterdepolarization; ERP, effective refractory period; HCN, hyperpolarization-activated cyclic nucleotide-gated; RyR2, ryanodine receptor 2; SAN, sino-atrial

node; SQTS, short-QT syndrome; and SR, sarcoplasmic reticulum.

Table 1. Continued

Class Subclass

Pharmacological

Targets Electrophysiological Effects

Examples of

Drugs

Major Clinical

Applications

Corresponding

Likely Therapeutic

Mechanism(s)

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1886

STATE OF THE ART

lar targets and cellular physiological mechanisms related

to Ca2+ homeostasis. Further new classes reﬂect addi-

tional targets that have been identiﬁed since the original

Vaughan Williams classiﬁcation. They include cardiac au-

tomaticity (Class 0) and recently demonstrated drugs act-

ing on mechanically sensitive channels (Class V) or medi-

Figure 1. Surface and intracellular membrane ion channels, ion exchangers, transporters, and ionic pumps involved in cardiomyocyte

electrophysiological excitation and activation.

A, Their grouping by pharmacological targets listed in Table 1. B through E, Activation and inactivation of ion channels, currents, underlying proteins, and

encoding genes and their contributions to (B) inward depolarizing and (C) outward repolarizing currents bringing about cardiac action potentials (APs).

Ventricular (D) and atrial (E) APs comprise rapid depolarizing (phase 0), early repolarizing (phase 1), brief (atrial) or prolonged (ventricular) phase 2 plateaus

(phase 2), phase 3 repolarization, and phase 4 electric diastole. In these, inward Na+ or Ca2+ currents drive phase 0 depolarization and Ca2+ current maintains

the phase 2 plateau (B), and a range of outward K+ currents (C) drive phase 1 and phase 3 repolarization. Phase 4 resting potential restoration is accom-

panied by a refractory period required for Na+ channel recovery. The resulting wave of electric activity and refractoriness is propagated through successive

sino-atrial node, atrial, atrioventricular, Purkinje, and endocardial and epicardial ventricular cardiomyocytes. CaMKII indicates calcium/calmodulin kinase II; Cx,

connexin; Gi, inhibitory G protein; Gs, stimulatory G-protein; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; Nav1.5, cardiac Na+ channel

protein; PKA, protein kinase A; RyR2, cardiac ryanodine receptor type 2; and TRP, transient receptor potential channel. Adapted from Huang19 with permis-

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STATE OF THE ART

ating electrotonic coupling between cells (new Class VI).

Finally, a range of signaling processes exert longer-term

effects on arrhythmic tendency through modifying struc-

tural remodeling (Class VII). These classiﬁcation activities

are now discussed brieﬂy in turn.

These diverse drug actions converge on a deﬁned set

of distinct cellular and tissue electrophysiological end ef-

fects bearing on the respective cardiac properties of au-

tomaticity, AP generation, and AP conduction (Table 1,

right column).7 Changes in the automaticity responsible

for spontaneous, rhythmic cardiac activity can arise from

abnormalities in the repetitive SAN activity, depending on

its pacemaker currents. It can also arise from subsidiary

pacemaker formation in specialized conducting AVN or

Purkinje ﬁbers and from normally nonautomatic atrial

and ventricular cardiomyocytes when they are depolar-

ized by some pathological processes. In the case of trig-

gered activity that generates ectopic APs, early afterdepo-

larization phenomena occur during late phase 2 or early

phase 3 of often prolonged APs. The latter are particularly

associated with prolonged clinical QT intervals observed

under conditions of increased inward late Na+, L-type

Ca2+, decreased repolarizing outward K+ currents, or in-

creased depolarizing Na+/Ca2+ exchange current arising

from spontaneous sarcoplasmic reticular (SR) Ca2+ release

(Figure1B). In contrast, delayed afterdepolarizations af-

ter full AP repolarization are associated with situations of

intracellular Ca2+ overload, resulting in elevated SR Ca2+

or increased cytosolic Ca2+ sensitivity in the cardiac ryano-

dine receptor (RyR2). Either situation predisposes to spon-

taneous SR Ca2+ release. This increases cytosolic [Ca2+],

which in turn transiently increases inward depolarizing

Na+/Ca2+ exchange current.

These triggering events may produce persistent ar-

rhythmia whether through their perpetuating further

such events or through arrhythmic substrate facilitat-

ing reentry of excitation from active into recovered

myocardial regions. This takes place in the presence of

heterogeneities that generate obstacles to AP conduc-

tion, around which the AP circulates with slowed con-

duction velocities that may reﬂect altered ion channel

or myocardial tissue electric properties. The result is a

formation of multiple, heterogeneous pathways of im-

pulse propagation between anatomically or function-

ally deﬁned points in the heart.62 Whereas an anatomic

Table 2. Examples of Multiple Actions of Cardiac

Electrophysiologically Active Drugs

Class

0 HCN channel blockers15,24–27

Ivabradine IKr antagonism and slowed atrioventricular conduction

in addition to If antagonism

I Voltage-gated Na+ channel blockers16,24–29

Quinidine Ito, IKr, IKs, IK1, IKATP, ICa, autonomic α-adrenergic, and

cholinergic in addition to Class Ia antagonism

Disopyramide Ito, IKr, IK1, IKATP, and cholinergic in addition to Class

Ia antagonism; negative inotropic but no α- or β-

adrenergic effects

Procainamide IKr, IK1, IKATP, and autonomic ganglion in addition to

Class Ia antagonism

Lidocaine No IK effects

Mexiletine No IK effects

Flecainide IKur, IKr, ICa and RyR2 in addition to Class Ic

antagonism

Encainide IKur and IKr in addition to Class Ic antagonism

Propafenone IKur, IKr, ICa, RyR2, autonomic β-adrenergic and vagal in

addition to Class Ic antagonism

Ranolazine IKr in addition to Class Ic antagonism

II Autonomic inhibitors and activators5,16,24–27,29

Carteolol Increased nitric oxide production in addition to Class

IIa antagonism

Carvedilol Possible antioxidant activity; ICaL, RyR2-Ca2+ channel,

and α1-adrenergic in addition to Class IIa antagonism

Propranolol INa in addition to Class IIa antagonism

Betaxolol ICaL in addition to Class IIb antagonism

Celiprolol Increased nitric oxide production, partial β2-

adrenergic agonist, and weak α2-adrenergic

antagonist effects in addition to Class IIb antagonism

Nebivolol Increased nitric oxide production in addition to Class

IIb antagonism

III K+ channel blockers and openers16,24–27,29,42

Dofetilide Often considered “pure” IKr blocker

Ibutilide INa activation in addition to IKr antagonism

d/l-Sotalol Ito, IK1, and β-adrenergic in addition to IKr antagonism

Cloﬁlium Ito and IK1 in addition to IKr antagonism

Amiodarone INa, ICa, Ito, IKs, IK1, IKACh, α- and β-adrenergic in addition

to IKr antagonism; reduced automaticity

Dronedarone IKs and β1-adrenergic in addition to IKr antagonism

Vernakalant INaL in addition to IKur antagonism

Tedisamil IKr and IKATP in addition to Ito antagonism

Nicorandil Nitrate action vasodilating vascular smooth muscle in

addition to IKATP antagonism

Rimakalim Nitrate action vasodilating vascular smooth muscle in

addition to IKATP antagonism

(Lev)

cromakalim

Nitrate action vasodilating vascular smooth muscle in

addition to IKATP antagonism

IV Ca2+ handling modulators5,16,24,26,27,29

Verapamil Vascular smooth muscle (tachycardic effects) in

addition to cardiac ICaL antagonism (bradycardic

effects), reduced DADs

(Continued )

Diltiazem Vascular smooth muscle (tachycardic effects) in

addition to cardiac ICaL antagonism (bradycardic

effects), reduced DADs

Bepridil Vascular smooth muscle (tachycardic effects) in

addition to cardiac ICaL antagonism (bradycardic

effects), reduced DADs

DAD indicates delayed afterdepolarization; HCN, hyperpolarization-activated

cyclic nucleotide-gated; and RyR2, ryanodine receptor 2.

Table 2. Continued

Class

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1888

STATE OF THE ART

reentry of excitation takes place around a central inex-

citable anatomic obstacle, a functional reentry of exci-

tation involves a functional central obstacle. Reentrant

excitation is also facilitated by abnormalities leading

to heterogeneities in AP recovery arising from relative

changes in ERP and APD, whether early (phase 2)63–65

or late in the time course of AP repolarization.19,23,66,67

NEW CLASS 0 OF DRUGS ACTING ON

SINO-ATRIAL AUTOMATICITY

Detailed characterizations of the properties of SAN cells

postdated the original Vaughan Williams classiﬁcation.10

SAN cells are exceptional in showing automaticity un-

der normal physiological conditions, with contributions

from a “membrane clock” giving rise to a spontaneous

diastolic depolarization described as the pacemaker po-

tential. This is driven by a net inward current, to which

the most important contribution may be the “funny

current” (If) carried by hyperpolarization-activated cyclic

nucleotide-gated channels, particularly during the initial

phase of the diastolic depolarization.12,14,68 The only cur-

rently clinically adopted Class 0 agent, ivabradine, is used

to reduce heart rates in situations of inappropriate sinus

tachycardia69,70 or when sinus tachycardia accompanies

cardiac failure.71 It likely acts through hyperpolarization-

activated cyclic nucleotide-gated channel block, with

possible additional effects on intracellular Ca2⁺ cycling.72

Future investigations may explore the extent to which

diastolic depolarization is further augmented by deacti-

vation of outward delayed rectiﬁer K+ current and ac-

tivation of inward currents, including Na+-dependent

background current (IbNa), T- and L-type Ca2+ currents (ICaL

and ICaT),73 and possibly sustained inward current (Ist). In-

ward voltage-dependent Na+ current (INa) has also been

recorded from SAN pacemaker cells, although it may be

inactivated at the relatively positive potentials during the

pacemaker potential in the SAN.13,14 In addition, intracel-

lular signaling involving SR Ca2+ stores, cellular cAMP lev-

els, and consequent phosphorylation of their signaling

proteins has recently been implicated in a “Ca2+ clock” in

which spontaneous RyR2-mediated Ca2+ release enhanc-

es electrogenic Na+/Ca2+ exchanger activity during both

SAN14,74,75 and Purkinje cell diastolic depolarization.76

EXTENSION OF VAUGHAN WILLIAMS

CLASS I

Our revised classiﬁcation system retains the 3 original

Class I subcategories listing cardiac Na+ channel (Nav1.5)

blockers.16,30 However, it incorporates recent biophysical

ﬁndings bearing on gating transitions regulated by volt-

age sensing components of Nav1.5 (Table 1).77 Nav1.5

is preferentially expressed in atrial, Purkinje conducting,

and ventricular as opposed to SAN and AVN cardiomyo-

cytes. AP initiation then involves regenerative transitions

from the resting state of Nav1.5 to its active state that

permits the inward Na+ current (INa), responsible for phase

0 rapid depolarization (Figure2). The depolarization also

causes the subsequent transition of Nav1.5 into an inac-

tivated state, resulting in channel refractoriness. Channel

recovery from the inactivated to the resting state then

requires membrane repolarization and takes place over a

ﬁnite time course.17,22 Class Ia drugs subsequently proved

to show concomitant effects on other, particularly K+,

channel species, with potential consequences for Class

III actions related to late depolarizing events.78 Neverthe-

less, we retain their original Class Ia subclassiﬁcation as

Na+ channel blockers, with all drugs in Classes Ia through

1c reducing AP maximum upstroke rates (dV/dt)max and

AP conduction in atria, ventricular, and conducting tissue

despite different effects on APD (Figure2).

Class Ia drugs preferentially bind to the open state of

Nav1.5 with dissociation time constants (τ) of ≈1 to 10

seconds. They thus reduce AP conduction velocity and

increase ERP. Concomitant K+ channel block by Class Ia

drugs also increases APD. Together, these properties re-

duce reentrant tendency. In contrast, Class Ib drugs bind

preferentially to the Nav1.5 inactivated state from which

they dissociate relatively rapidly with a τ of ≈0.1 to 1.0

second. This minimizes perturbations of processes in the

remaining cardiac cycle and explains the effectiveness

of Class 1b drugs in preventing arrhythmias, particularly

in ventricular tissue, where Nav1.5 channels remain in-

active for the longest duration. Class Ib drugs result in

shortening of both APD and ERP in normal ventricular

muscle and Purkinje cells16 but cause prolongation of

ERP and consequently prolongation of postrepolariza-

tion refractoriness in ischemic, partially depolarized,

cells.79 Class Ic drugs similarly bind to the inactivated

Nav1.5, from which, however, they dissociate more

slowly, over τ >10 seconds. Use-dependent channel

block in Classes Ia through 1c arises from accumula-

tion of blocked channels during repetitive stimulation

at high frequencies and accordingly occurs to extents in

the sequence Class Ic>Class Ia>Class Ib. This results in

a generalized reduction in cardiac excitability with non-

speciﬁc and widespread effects. These include slowed

AP conduction with increased APD at high heart rates

and possible reductions in cardiac automaticity.16

These differing dissociation rates shown by Class Ia,

Ib, and Ic agents also result in contrasting effects on AP

conduction reﬂected in the associated normal and pro-

longed QRS durations, at least under conditions of nor-

mal cardiac rhythm. The different properties of Class I

drug subgroups thus result in differing clinical effects,

varying with the particular electrophysiological condi-

tions underlying the targeted arrhythmias. The rela-

tively slow dissociation of the Class Ic agent ﬂecainide,

from its binding to the inactivated state of Nav1.5,

compromises AP initiation and conduction. Flecainide

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STATE OF THE ART

is thus antiarrhythmic, with the compromised AP re-

covery, gain of Na+ channel function, and increased

INaL in both clinical LQTS3 and genetically modiﬁed

murine Scn5a+/∆kpq hearts experimentally modeling this

condition.23 In contrast, ﬂecainaide was clinically pro-

arrhythmic under conditions of compromised postin-

farct AP generation and propagation (Table 3)80 and

the Brugada syndrome and in murine Scn5a+/− mod-

els that replicate its associated loss of Nav1.5 function

and age-dependent ﬁbrotic changes.18–21 This also con-

trasts with the respective antiarrhythmic actions of the

more rapidly dissociating Class Ia and Class Ib agents

quinidine and lidocaine in situations of compromised

AP generation and propagation. Quinidine is addi-

tionally proarrhythmic under conditions of prolonged

AP recovery, at least partially reﬂecting its additional

IK-blocking effects. The different Class I actions also

inﬂuence their clinical indications for arrhythmias af-

fecting different regions of the heart. Finally, because

atrial Nav1.5 channels remain open for longer than in

the ventricles, Class Ia (exempliﬁed in Table 1 by quini-

dine, ajmaline, and disopyramide) and Ic (exempliﬁed

Figure 2. Relationships between biophysical actions of Class I drugs on cardiac Na+ channel protein (Nav1.5) and their consequent electrophysiological

antiarrhythmic and proarrhythmic effects.

A, Initial depolarization activates the Nav1.5 voltage sensor, in turn causing a transition from its resting, closed, to its open state, permitting extracellular Na+ inﬂux

through the selectivity ﬁlter of the channel. The resulting regenerative depolarization results in slower transitions into an inactivated state, causing channel closure,

from which recovery to the resting state requires membrane potential repolarization. The different Class Ia through Id drugs act at different stages in this reaction

cycle and on differing early, INa, and late, INaL, Na+ current components. This results in (B) differential actions on action potential (AP) conduction, triggering, and

duration, with proarrhythmic or antiarrhythmic effects, depending on the background clinical conditions. BrS indicates Brugada syndrome; DAD, delayed afterde-

polarization; EAD, early afterdepolarization; and LQTS, long-QT syndrome.

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1890

STATE OF THE ART

here by propafenone and ﬂecainide) drugs are useful in

preventing supraventricular arrhythmias.30

Finally, actions of drugs such as ranolazine, GS-

458967, and F15845 in the new Class Id differ sharply

from those in Classes Ia through 1c. They inhibit the

relatively small but persistent late Na+ current (INaL) that

follows the principal rapidly inactivating INa decay and

inﬂuences AP shape and duration. This increases in ac-

quired or congenital proarrhythmic conditions, includ-

ing hypoxia, heart failure, and LQTS3. These drugs thus

shorten AP recovery and increase refractoriness and

repolarization reserve. Both clinical and experimental

reports suggest that they have potential antiarrhythmic

effects in INaL-related arrhythmia.32,81,82 Class Id effects

may also contribute to multiple drug actions. This ef-

fect is found with mexiletine, originally placed in Class

Table 3. Examples of Common Proarrhythmic Actions of Antiarrhythmic Pharmacological Drugs

Class Arrhythmia Likely Mechanisms

0 Hyperpolarization-activated cyclic nucleotide-gated channel blockers15

Ivabradine Sinus bradycardia Depressing sinus node automaticity by block of If

I Voltage-gated Na+ channel blockers16,24–29

Quinidine Torsades de pointes with prolonged QT interval; vagolytic effect with

increase in ventricular rate in atrial ﬂutter

EAD-related triggered activity

Conduction slowing in the atrium with

enhanced or unaltered atrioventricular

conduction

Disopyramide Torsades de pointes with prolonged QT interval EAD-related triggered activity

Procainamide Torsades de pointes with prolonged QT interval

Ventricular tachycardia in the presence of ischemic heart disease

EAD-related triggered activity

Conduction slowing in the ventricle

Flecainide Increase in ventricular rate in atrial ﬂutter

Ventricular tachycardia in the presence of ischemic heart disease or old

myocardial infarction

Conduction slowing in the atrium with

enhanced or unaltered atrioventricular

conduction

Conduction slowing in the ventricle or

myocardial scar areas

Propafenone Increase in ventricular rate in atrial ﬂutter

Ventricular tachycardia in the presence of ischemic heart disease or old

myocardial infarction

Slowed sinus rate

Conduction slowing in the atrium with

enhanced or unaltered atrioventricular

conduction

Conduction slowing in the ventricle or

myocardial scar areas

Depressing sinus node automaticity by block of If

II Autonomic inhibitors and activators5,16,24–27,29,34

β-Adrenergic receptor

inhibitors

Sinus bradycardia; atrioventricular block

Sinus tachycardia or other type of tachycardia

β-Blockade

Upregulation of β-receptors with long-term

therapy; β-blocker withdrawal

β-Adrenergic receptor

activators

Sinus tachycardia, increased triggering activity β-Receptor activation

M2 receptor activators:

carbachol, digoxin

Sinus bradycardia; atrioventricular block;

ventricular tachycardia

Depression of SAN automaticity and

atrioventricular node conduction

Increase in vagal tone

Increased delayed afterdepolarization–related

triggered activity

M2 receptor inhibitors: atropine Exacerbated ventricular bradycardia and exacerbated effects of low

atrioventricular block

Increased SAN automaticity and atrioventricular

conduction despite persistent degenerative

atrioventricular block at or below His bundle

level

A1 receptor activators:

adenosine

Sinus bradycardia, sinus arrest, or atrioventricular block associated with

adenosine terminating paroxysmal supraventricular tachycardia

Frequent atrial or premature ventricular beats; atrial ﬁbrillation

Depressing sinoatrial node automaticity and

atrioventricular node conduction

Unknown mechanism

III K+ channel blockers and openers16,24–27,29

Dofetilide, ibutilide, d/l-sotalol Torsades de pointes with prolonged QT interval EAD-related triggered activity

IV Ca2+ handling modulators5,16,24,26,27,29

Ca2+ channel blockers eg,

verapamil

Sinus bradycardia; atrioventricular block

Increase in ventricular rate in patients with atrial ﬁbrillation with Wolff-

Parkinson-White syndrome

Depressing SAN automaticity and

atrioventricular node conduction by block of

Ca2+ channel; decreased accessory pathway

EAD indicates early afterdepolarization.

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STATE OF THE ART

Ib, and makes it useful in management of not only

LQTS378,83,84 but also Timothy syndrome, associated

with L-type Ca2+ channel abnormality.85

EXTENSION OF VAUGHAN WILLIAMS

CLASS II

We similarly retain the Vaughan Williams Class II but

extend its coverage beyond an updated range of sym-

pathetic β-adrenergic effects to further include parasym-

pathetic targets.5 This thereby provides more complete

coverage of autonomic effects as a whole, including

actions through cell surface membrane guanine nucleo-

tide-binding protein (G-protein)–coupled receptors. First,

Vaughan Williams would have been aware of the end ef-

fects but not the detailed mechanisms of β-adrenergic re-

ceptor activation through increased cytosolic [cAMP]i af-

ter successive Gs-protein and adenylate cyclase activation.

The increased [cAMP]i activates protein kinase A, which

phosphorylates a wide range of ion channels, including

Nav1.5, the K+ channel species Kv11.1, Kv7.1 (mediating

the rapid and slow K+ currents, IKr and IKs respectively),

Cav1.2, and Cav1.3 (mediating L-type Ca2+ currents), and

RyR2. cAMP also exerts a direct inﬂuence on hyperpolar-

ization-activated cyclic nucleotide-gated channel activity

and consequently on the pacemaking If. Finally, exchange

proteins directly activated by cAMP have been reported

to trigger RyR2-mediated Ca2+ release.19

These actions together produce multiple inotropic,

chronotropic, and lusitropic effects on cardiac func-

tion.33,53 Table 1 places the clinically used nonselec-

tive and selective β1-adrenergic receptor inhibitors

carvedilol and propranolol (nonselective) and atenolol

(selective), indicated in a wide range of tachyarrhyth-

mias, in Class IIa. These often act through inhibiting

Ca2+ entry and SR Ca2+ release and their consequent

proarrhythmic early afterdepolarization– or delayed

afterdepolarization–induced triggered activity. The clas-

siﬁcation also places nonselective β-adrenergic recep-

tor activators, exempliﬁed by isoproterenol, in Class

IIb. The latter contrastingly activate Ca2+ entry and SR

Ca2+ release, potentially accentuating proarrhythmic

early afterdepolarization–induced triggered activity.

However, their chronotropic effects usefully accelerate

rates of ventricular escape rhythm in the management

of complete atrioventricular block before pacemaker

implantation.34 Such acceleration of depressed heart

rates and relief of prolonged postextrasystolic pauses

may additionally suppress bradycardia-dependent early

afterdepolarizations. Isoproterenol thus exerts antiar-

rhythmic effects in bradycardia-dependent, drug- or

atrioventricular block–related, and possibly congenital

LQTS type 2– and LQTS3-related torsades de pointes

but proarrhythmic effects in adrenergic dependent or

LQTS type 1–related torsades de pointes.86

Second, of the large range of further G-protein sub-

types, Gi proteins mediate parasympathetic cholinergic

muscarinic (M2) or adenosine (A1) receptor activation.

Their activation and inhibition reduce and increase

membrane excitation, respectively, particularly under

conditions of preexisting adenylyl cyclase activity, affect-

ing chronotropic and conduction function. Table 1 intro-

duces M2 inhibitors in the new Class IIc, exempliﬁed by

atropine, indicated for relieving sinus bradycardia and

supra-His (Table 1), although not degenerative, atrio-

ventricular block at or below the His bundle level (Table

3). Table 1 also illustrates drugs inhibiting Gi exempliﬁed

by carbachol and adenosine in new Classes IId and IIe,

respectively, while bearing in mind the brief period of in-

travenous adenosine action and its tendency to produce

atrial ﬁbrillation.87 It also cites an action of aminophylline

in adenosine receptor block, useful to treat bradycardia

associated with sinus node dysfunction.88 The latter ac-

tions take place in the SAN, AVN, or atrial myocardium

even in the absence of sympathetic stimulation but in

ventricular tissue take place only after adrenergic activa-

tion. Thus, drugs activating Gi are normally effective in

SAN, atria, or AVN tachycardias but are effective only in

adrenergically stimulated Purkinje or ventricular cells. Gi

activation opens inward rectifying IKACh or IKAdo channels

mediated by βγ subunits of the G protein, particularly in

supraventricular tissue, through actions on their GIRK1

and GIRK4 components.35,89,90 Gi activation also inhib-

its adenylyl cyclase, which reduces [cAMP]I; therefore

cAMP-associated increases in ICaL and If. Gi activation

may also upregulate protein phosphatase 2–mediated

dephosphorylation at protein kinase A phosphoryla-

tion sites on inwardly rectifying K+ channels, L-type Ca2+

channels, RyR2s, phospholamban, troponin subunit car-

diac troponin I, and cardiac-type myosin-binding protein

C.36,37 Finally, ≈150 of the large number of additional

potential G protein–coupled receptors remain orphan

receptors that might offer potential therapeutic targets.

EXTENSION OF VAUGHAN WILLIAMS

CLASS III

Much progress has also followed the original Vaughan

Williams classiﬁcation42 resulting from increased knowl-

edge of K+ channel subtypes. More is also known about

the α and auxiliary β subunits, selective localization of K+

channels in particular cardiac regions, and roles of these

channels in AP recovery and membrane potential stabili-

zation (Figure1B and Table 1).35,41 After phase 0 depolar-

ization, complex components of transient inward current

(Ito) contribute to early rapid phase 1 AP repolarization.

These include rapidly activating and inactivating Kv4.3-

and Kv4.2-mediated fast inactivating Ito,f and Kv1.4-medi-

ated and slowly inactivating Ito,s, which become activated

at potentials of >−30 mV. Atrial myocytes show particu-

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1892

STATE OF THE ART

larly prominent Ito, and an atrium-speciﬁc Kv1.5 (KCNA5)

mediates ultrarapid IKur. In addition, there is a 6-fold great-

er expression of GIRK1 and GIRK4 proteins that mediate

IKACh. These multiple K channel contributions together

result in the shorter atrial compared with ventricular APs.

Kv11.1 (HERG or KCNH2) mediating IKr rapidly activates

with phase 0 AP depolarization but then rapidly inacti-

vates over AP phases 0 to 2. The onset of phase 3 repolar-

ization reverses this inactivation, reopening the channel

leading to outward phase 3 and early phase 4 currents

terminating the AP plateau. The channel responsible for

IKr is more greatly expressed in human ventricular than

atrial cardiomyocytes and in left than right canine atrial

cardiomyocytes. In contrast, Kv7.1 (KCNQ1) mediating IKs

requires depolarization to a more positive potential for

activation, which then takes place relatively slowly. IKs in-

creases over phase 2 to become a major phase 3 K+ con-

ductance that barely inactivates. It is expressed uniformly

in canine atria but at a higher density in epicardial and

endocardial cells than M cells and in right ventricular than

left ventricular M cells with possible implications for pro-

arrhythmic LQTS.40,43 Inward rectifying IK1, mediated by

Kir2.1, Kir2.2, and Kir2.3 (KCNJ2, KCNJ12, and KCNJ4),

reﬂects reductions in K+ conductance at membrane po-

tentials more depolarized than ≈−20 mV, as occurs in

phases 0 to 2 of the AP. This reduces the net depolar-

izing inward currents required to maintain the AP plateau

phase. In contrast, the K+ conductance becomes greater

when the AP recovers to membrane potentials more hy-

perpolarized than ≈−40 mV. This results in the increased

K+ outward current, which in turn facilitates late phase

3 AP repolarization. This channel also stabilizes phase 4

diastolic resting potentials. It occurs at a higher density in

human ventricular than atrial myocytes.

Finally, the metabolically dependent IKATP is normally

small but is activated by reduced intracellular ATP levels

when it results in triangulation of AP waveforms.44 The

K2P2.1 (KCNK2, expressing K2P currents) and the ATP-sensi-

tive Kir6.2 (KCNJ11) mediating IKATP show little time or volt-

age dependence but contribute background currents reg-

ulating resting membrane potentials and cell excitability.

The more extensive group of clinical Class III agents

now includes wider ranges of voltage-dependent K+ chan-

nel blockers (Class IIIa), including nonselective (ambasilide,

amiodarone) and selective (HERG; IKr; dofetilide, ibutilide,

sotalol) Kv11.1, Kv1.5 (IKur; vernakalant), and KV1.4 and

KV4.2, (Ito1: tedisamil) blockers, as well as important drugs

opening metabolically dependent (Kir6.2: IKATP: nicorandil,

pinacidil; Class IIIb) and investigational drugs blocking

transmitter-dependent (GIRK1 and GIRK4: IKACh; BMS

914392; Class IIIc) K+ channels. These may act directly

on the channels concerned or involve further indirect ef-

fects such as those exempliﬁed by the inhibitory actions of

dofetilide on phosphoinositide 3-kinase signaling, in turn

inhibiting IKr and increasing INaL.91,92 In addition, a number

of agents with multiple actions are included here (Table 2).

Amiodarone and dronedarone show diverse actions even

at therapeutic concentrations and complex therapeutic

and toxicity proﬁles but ﬁnd widespread use in managing

atrial ﬁbrillation (Table 2). Finally, the signiﬁcant K+ chan-

nel and therefore Class III actions demonstrated for the

original Class Ia agents have been recognized. Thus, al-

though quinidine was originally placed in Class I, its clini-

cal antiarrhythmic effects in Brugada syndrome probably

include inhibition of Ito.63 It has been suggested that this

involves reductions in the transmural dispersions of ven-

tricular repolarization that arise from the greater epicardial

than endocardial expression of Ito, which results in the nor-

mally shorter epicardial relative to endocardial APDs.23,64,66

Further examples of agents with such multiple actions are

listed in Table 2. Finally, K+ itself inﬂuences K+ channel per-

meabilities with important effects on resting membrane

potential stability and APD.23

EXTENSION OF VAUGHAN WILLIAMS

CLASS IV

Much recent physiological progress has broadened the

range of drugs included as Vaughan Williams Class IV

drugs, originally deﬁned as drugs blocking Ca2+ entry

through speciﬁc Ca2+ channels. Here, we have extend-

ed Class IV to include drugs with a variety of actions

that can be described as Ca2+ handling modulators. The

L-type voltage-gated Ca2+ current (ICaL) emerges with

roles in both atrial and ventricular cardiomyocyte func-

tion and in AP conduction in the AVN. It thus both con-

tributes to the ventricular and atrial AP plateau phases

and initiates excitation-contraction coupling. ICaL brings

about an initial cytosolic [Ca2+] elevation that triggers

the Ca2+-induced release of SR Ca2+ by intracellular RyR2

Ca2+ release channels. The resulting further elevations

of cytosolic [Ca2+] in turn drive contractile activation. An

inositol trisphosphate (IP3)–triggered Ca2+ release that

has been implicated in atrial arrhythmia may also exist.

After AP recovery, cytosolic [Ca2+] is returned to resting

levels by Ca2+ transport from cytosol to SR lumen by phos-

pholamban-regulated SR Ca2+-ATPase33 and from cytosol

to extracellular space by plasma membrane Ca2+-ATPase

and by surface membrane ion exchangers, particularly

sarcolemmal Na+/Ca2+ exchange.53 Of these, Na+/Ca2+ ex-

change involves electrogenic entry of 3 Na+ for each Ca2+

extruded. Depending on the membrane potential and

submembrane [Ca2+] that determine the driving forces on

Na+ and Ca2+ ﬂuxes, this can exert depolarizing effects.

Activity in a signiﬁcant proportion of these mem-

brane and cytosolic signaling and Ca2+ transport mol-

ecules is altered by kinase-mediated phosphorylation

and phosphatase-mediated dephosphorylation.55,56

These opposing processes are in turn modiﬁed by cyto-

solic, often Ca2+-sensing, signaling molecules also offer-

ing potential pharmacological targets. Besides protein

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STATE OF THE ART

kinases A and C, these include calmodulin and calcium/

calmodulin kinase II.44,50,56,57 Modiﬁcations in 1 or more

of these processes in turn altering cytosolic [Ca2+] have

been implicated in both atrial and ventricular clinical ar-

rhythmias.51,52 In particular, Na+/Ca2+ exchange exerts

electrogenic effects that can increase to become poten-

tially proarrhythmic with cellular Ca2+ overload.5,48

The central importance of Ca2+ homeostasis to cardiac

electrophysiological activity with extensive ﬁndings after

the original Vaughan Williams classiﬁcation accounts for

a wide range of potential applications directed at clini-

cal arrhythmia (Table 1). Besides nonselective (bepridil)

and Cav1.2/Cav1.3 (ICaL)–selective (verapamil, diltiazem)

Ca2+ channel blockers (Class IVa), Mg2+, although not

strictly falling within the category of a drug, also exerts

Ca2+ channel blocking and membrane stabilizing effects,

with applications in treatment of torsades de pointes.

In recent reports, the Class Ic agent ﬂecainide and the

Class IIa agent carvedilol show additional Class IVb ac-

tions in reducing RyR2-mediated SR Ca2+ release. This

proved potentially applicable in the management of

catecholamine-sensitive polymorphic ventricular tachy-

cardia, whether through reduced triggering activity or

reversing associated proarrhythmic reductions in INa.93–95

Possible clinical applications of decreasing cardiac myo-

sin heavy chain– or SR Ca2+ reuptake–related ATPase

activity (Class IVc) have prompted explorations of the

investigational new drugs MYK-46196 and istaroxime97

in hypertrophic cardiomyopathy and cardiac failure, re-

spectively. Possible applications will also likely emerge

from drugs modifying Na+/Ca2+ exchange (Class IVd)

and phosphorylation of proteins involving Ca2+ homeo-

stasis, including calcium/calmodulin kinase II (Class IVe)98

(Table III in the online-only Data Supplement).

NEW CLASS V OF DRUGS ACTING ON

MECHANOSENSITIVE CHANNELS

Class V is introduced to include mechanosensitive chan-

nel blockers. These are selective for cation-selective and

mechanosensitive ion channels, particularly transient

receptor potential channels (TRPCs) such as TRPC3 or

TRPC6. Multiple subclasses of TRPCs exist in the heart,

although their functions are only now beginning to

emerge. They potentially suppress abnormal ectopic or

triggered activity in cardiac conditions such as cardiac hy-

pertrophy and heart failure.58 A TRPC subclass may regu-

late the cardiac hypertrophic response. Although TRPCs

allow permeation by a range of different cations, their

speciﬁc biological functions have generally been attrib-

uted to Ca2+ inﬂux, resulting in signaling within local do-

mains, direct interactions with Ca2+-dependent regulatory

proteins, or regulation of cardiac ﬁbroblastic Ca2+ signals

in arrhythmic hypertrophic and ﬁbrotic heart disease and

cardiac failure.58 Accordingly, inhibition of TRPC-mediat-

ed Ca2+ inﬂux could potentially both exert direct antiar-

rhythmic effects and attenuate replacement ﬁbrosis after

cardiomyocyte death. Such an approach is being explored

with a number of investigational drugs, including ACA

[N-(p-amylcinnamoy)anthranilic acid], GSK2332255B,

GSK2833503A, pyrazole-3, GsMTx4, and SKF 96365

(Table III in the online-only Data Supplement).

NEW CLASS VI OF DRUGS ACTING ON

CONNEXIN-ASSOCIATED CHANNELS

AP conduction depends on intercellular local circuit

current spread involving gap-junction conductances

containing apposed connexin (Cx) hemichannels elec-

trically connecting the intracellular spaces of adjacent

cardiomyocytes.62 This possible therapeutic direction is

being investigated with both Cx-blocking and -opening

agents, exempliﬁed by carbenoxalone and the peptide

analog rotigaptide (ZP-123), respectively, the latter in

connection with potential treatments for atrial ﬁbrillation

(Table III in the online-only Data Supplement). Of cardiac

Cx isoforms, Cx40 occurs in atrial myocytes, AVN, and

the Purkinje conduction system. Cx43 occurs in both

atrial and ventricular myocytes and the distal conduc-

tion system. Cx45 occurs mainly in the SAN, AVN, and

Purkinje conducting system. Blocking gap junction con-

ductance or expression, depending on circumstances,

can enhance or reduce arrhythmogenicity. Changes in

gap junction function can accompany alterations in oth-

er AP conduction determinants such as ﬁbrotic change

or other remodeling processes in which these are ac-

companied by altered excitability. Plasticity reducing and

lateralizing Cx43 expression occurs in both hypertrophic

and dilated ventricular cardiomyopathies.18,59

NEW CLASS VII OF DRUGS ACTING ON

UPSTREAM MODULATORY TARGETS

The introduction of a Class VII results from the need to

encompass tissue structure remodeling processes and

their consequently longer-term changes that contrast

with the primary preoccupation with the short-term

effects of particular drugs on speciﬁc ion channels in

the original Vaughan Williams classiﬁcation. In addi-

tion, molecular mechanisms inﬂuencing longer-term

changes upstream of the electrophysiological process-

es also constitute novel potential therapeutic targets.

Fibrotic change is an important accompaniment to

postinfarct healing, potentially leading to chronic scar-

related arrhythmogenesis, pressure overload,99 and the

development of atrial ﬁbrillation.47,60,61 It also accompa-

nies some Na+ channelopathies.18 Experimental studies

have demonstrated that renin-angiotensin-aldosterone

inhibitors, omega-3 fatty acids, and statins prevent

such electrophysiological and/or structural remodeling.

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Lei et al Reclassiﬁcation of Cardiac Antiarrhythmic Drugs

October 23, 2018 Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455

1894

STATE OF THE ART

These drugs are already available for indications such

as hypertension, coronary artery disease, and heart

failure, which are some of the most frequent causes

of atrial ﬁbrillation. Angiotensin-converting enzyme in-

hibitors or angiotensin-receptor blockers may be useful

in modifying the atrial substrate for primary or second-

ary prevention, reducing susceptibility to or progres-

sion of established atrial ﬁbrillation in the presence of

cardiac failure and hypertension. Statin therapy may be

useful for the primary prevention of new-onset atrial

ﬁbrillation after coronary artery surgery.25,60,61

RECAPITULATION

The revised classiﬁcation of antiarrhythmic drugs pre-

sented here summarizes current views of their electro-

physiological effects, which are categorized as princi-

pal (Table 1), subsidiary (Table 2), and proarrhythmic

(Table 3). It represents a pragmatic development of the

Vaughan Williams classiﬁcation (Table I in the online-

only Data Supplement). The revised scheme is consis-

tent with clinical actions of therapeutically established

drugs (Table 1 and Table II in the online-only Data Sup-

plement) and provides a classiﬁcation framework for

studies of new drugs under investigation (exempliﬁed

in Table III in the online-only Data Supplement).

ARTICLE INFORMATION

The online-only Data Supplement is available with this article at https://www.

ahajournals.org/doi/suppl/10.1161/circulationaha.118.035455.

Correspondence

Ming Lei, BM, MSc, DPhil, Department of Pharmacology, University of Oxford,

Mansﬁeld Rd, Oxford OX1 3QT, United Kingdom. Email ming.lei@pharm.

ox.ac.uk or Christopher L.-H. Huang, MA, BMBCh, DM, DSc, PhD, MD, ScD,

Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG, United

Kingdom. Email clh11@cam.ac.uk

Afﬁliations

Department of Pharmacology, University of Oxford, United Kingdom (M.L.,

D.A.T.). Department of Cardiology, Peking University First Hospital, Beijing,

China (L.W.). Physiological Laboratory (C.L.-H.H.) and Department of Bio-

chemistry (C.L.-H.H.). University of Cambridge, United Kingdom. Key Labora-

tory of Medical Electrophysiology of the Ministry of Education and Institute

of Cardiovascular Research, Southwest Medical University, Luzhou, China

(M.L., L.W.).

Acknowledgments

The authors thank Dr Qiqiang Jie at the Department of Cardiology, Peking Uni-

versity First Hospital, Beijing, China, for assistance with this article.

Sources of Funding

This work is supported by the Medical Research Council (MR/M001288/1

to Dr Huang, G10002647, G1002082 to Dr Lei), the Wellcome Trust

(105727/Z/14/Z to Dr Huang), the British Heart Foundation (PG/14/79/31102,

and PG/15/12/31280 to Dr Huang and PG/14/80/31106, PG/16/67/32340,

PG/12/21/29473, and PG/11/59/29004 to Dr Lei), the British Heart Foundation

Centres for Research Excellence at Cambridge (Dr Huang) and Oxford (Drs Lei

and Terrar), and the Chinese Nature Science Foundation (Drs Lei and Wu).

Disclosures

None.

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Introduction: This paper explores the potential influence of a single nucleotide variant in the ANK-2 gene on COVID-19 myocarditis-related ventricular tachycardia. Case Description: A 53-year-old female with a history of Crohn’s disease and asthma developed COVID-19. Shortly after infection, she experienced symptoms of chest pressure, palpitations, and shortness of breath, leading to the eventual diagnosis of myocarditis complicated by recurrent ventricular tachycardia. Treatment with mechanistically driven anti-arrhythmic therapy and beta-blockers suppressed this highly symptomatic ventricular tachycardia. Genetic testing to further risk stratify and influence long term care identified a single nucleotide variant in the ANK-2 gene, which is known to be associated with arrhythmic risk. Discussion: This case study highlights the use of rationally selected anti-arrhythmic therapy, mexiletine, in the management of ventricular tachycardia associated with COVID-19 myocarditis and the presence of a single nucleotide variant in ANK-2, raising the possibility of its contribution to VT susceptibility and severity. Our patient demonstrated significant improvement with administered therapeutics, including the resolution of myocarditis and ventricular tachycardia. The normalization of the QT interval during the resolution phase further supports the potential influence of the genetic variant in ANK-2 on potassium channel activity.

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Objective Aloperine (ALO) is an effective quinolizidine alkaloid. Previous research has demonstrated its antiarrhythmic effect by inhibiting voltage-gated sodium currents in rat ventricular myocytes. This study explored its effect on transient outward potassium currents (Ito) in rat atrial myocytes to identify potential targets in the context of ion channel currents. Methods The Ito characteristics in rat atrial myocytes were recorded using a whole-cell patch-clamp technique. Molecular docking was performed to validate ligand-protein binding interactions. Results ALO at concentrations of 3 and 10 μM significantly reduced Ito current densities. Gating kinetics analysis revealed ALO’s ability to slow Ito activation, hasten inactivation, and prolong transition from inactive to resting state. Molecular docking revealed that ALO could stably bind to KCND2. Conclusion ALO may inhibit Ito by slowing the activation process, accelerating inactivation, and delaying the recovery time after inactivation, potentially preventing acetylcholine-induced AF.

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This work outlines the development of a voltammetric method for a sensitive, rapid, and environmentally friendly determination of the antihypertensive sotalol (SOT) in several sample types employing the anodically pretreated boron‐doped diamond electrode. Cyclic voltammograms of SOT presented a well‐defined irreversible oxidation peak at 1.21 V (Ag/AgCl (3.0 mol L ⁻¹ KCl)) in Britton–Robinson buffer solution (pH 3.0). Figures of merits recommended by the validation guidelines were evaluated for the validation of the present method. Employing differential pulse voltammetry linearity of SOT was obtained in the concentration range of 0.39–4.22 μmol L ⁻¹ in 0.1 mol L ⁻¹ H 2 SO 4 solution, with a limit of detection of 0.031 μmol L ⁻¹ . The selectivity of the method was assessed against interferers and show relative standard deviation (RSD) values lower than 6 %. Recovery tests yielded percentages ranging from 93 % to 96 % in urine sample and from 100 % to 107 % in tap water sample. The proposed method was successfully applied in pharmaceutical, environmental, and biological samples offering a suitable green analytical chemistry profile.

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Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug–drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.

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Background The increasing use of intracardiac echocardiography (ICE) in the ablation of premature ventricular complexes (PVCs) has raised questions about its true efficacy and safety. Objective To evaluate the long-term outcome and periprocedural complications of PVCs ablation with and without ICE. Methods This retrospective study collected the periprocedural complications and PVC burden post ablation. The risk factors of PVC recurrence was further explored. Results The study included patients treated without ICE (control group, n=451) and with ICE (ICE group, n=155) from May 2019 to July 2022. The ICE group demonstrated significantly lower fluoroscopy times and X-ray doses. There were no major complications in the ICE group, and the difference in the occurrence of periprocedural complications between the groups was not statistically significant (p=0.072). The long-term success rates were similar for the control and ICE groups (89.6% and 87.1%, respectively). The origin of PVCs was identified as the independent factor for ablation success. Conclusions The use of ICE did not confer an advantage with regard to long-term success in PVCs ablation. To thoroughly evaluate the safety and effectiveness of ICE in PVCs ablation, a prospective, multicenter, randomized study is warranted.

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Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na⁺ current components play critical parts. Early peak, Na⁺ currents (INa) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na⁺ currents (INa-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of INa-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na⁺ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na⁺ channel abnormalities increasing INa-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate INa-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na⁺ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased INa-L.

Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart

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Background: -Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor (A1R) and its downstream GIRK channels (IK,Ado). Methods: -We applied bi-atrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and non-failing human hearts (n=37). Results: -Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100µM) produced more significant shortening of action potential durations (APD80) in RA (from 290±45ms to 239±41ms, 17.3±10.4%; p<0.01) than LA (from 307±24ms to 286±23ms, 6.7±6.6%; p<0.01). In ten hearts, adenosine induced AF (317±116 sec) that, when sustained (≥2 min), was primarily maintained by one/two localized reentrant drivers in lateral RA. Tertiapin (10-100nM), a selective GIRK channel blocker, counteracted adenosine-induced APD shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher A1R (2.7±1.7 fold; p<0.01) and GIRK4 (1.7±0.8 fold; p<0.05) protein expression than lateral/posterior LA. Conclusions: -This study revealed a three-fold RA-to-LA A1R protein expression gradient in the human heart, leading to significantly greater RA vs. LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest A1R/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.

2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society

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Article

Oct 2017

Background: Inappropriate sinus tachycardia (IST) is debilitating despite available treatment. Off-label use of ivabradine for IST prompted this systematic analysis of existing data quality and sample size estimates for adequately powered studies. Objective: To determine clinical efficacy of ivabradine in IST from pooled prospective studies. Methods: Analysis included ivabradine studies, for IST subjects without structural heart disease and follow-up of > 2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by various data instruments used in each study. Studies were assessed for quality using validated checklists. Sample sizes were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. Results: Nine studies met criteria, culminating in 145 patients pooled. Most patients were women (> 70%). Studies were small, not adequately powered and all reported a decrease in maximum and/or mean resting heart rate with complete/considerable amelioration of symptoms with ivabradine. Most studies had moderate quality with excellent consistency of study quality and narrow limits of agreement between the quality checklists. Sample size estimates for adequately powered studies various placebo effect and compared to β-blockade are reported. Conclusions: Ivabradine effectively reduces heart rate and symptoms in IST, but no studies were adequately powered to account for the expected placebo effect on symptoms. A multicenter-randomized, placebo controlled active and comparative study with a β-blocker are needed for confirmation. This is especially relevant given the ivabradine's potential teratogenic effect as many IST patients are females of childbearing potential.

Acquired Long QT Syndrome and Phosphoinositide 3-kinase

Article

May 2017

While it is well known that mutation of several different ion channels can cause congenital long QT syndrome, block of IKr is widely thought to be responsible for most cases of drug-induced acquired long QT syndrome (aLQTS). In this article, we review evidence supporting another cause of aLQTS due to inhibition of phosphoinositide 3-kinase (PI3K) signaling. Inhibition of PI3K affects multiple plateau currents, reducing IKr, IKs, and ICaL while increasing the persistent sodium current (INaP). The effects of PI3K inhibitors develop slowly, requiring hours to days to reach steady state. Dofetilide and terfenadine, an antihistamine on which much of the original IKr hypothesis was based, are among the many drugs that inhibit the PI3K pathway. Reduced PI3K signaling may also play a role in aLQTS associated with diabetes. Drug safety testing to identify aLQTS risk may be improved by examining PI3K-dependent effects that develop over time.

Murine Electrophysiological Models of Cardiac Arrhythmogenesis

Article

Jan 2017

Christopher L-H Huang

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca²⁺ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca²⁺ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.

Molecular Pathophysiology of Congenital Long QT Syndrome

Article

Jan 2017

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: Genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data

Article

Oct 2016

Background— The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current ( I Na and I NaL ), but ranolazine preferentially reduces I NaL . We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A . Methods and Results— We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation. We then performed a long-term clinical evaluation of ranolazine in LQT3 patients carrying the D1790G mutation. In the experimental study, I NaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of I NaL of the SCN5A-D1790G channel without reducing peak I Na significantly. In the clinical study, among 8 patients with LQT3 and confirmed D1790G mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from 509±41 to 451±26 ms, a mean decrease of 56±52 ms (10.6%; P =0.012). The QT-shortening effect of ranolazine remained effective throughout the entire study period of 22.8±12.8 months. Ranolazine reduced the QTc at all heart rates but less so during extreme nocturnal bradycardia. A type I Brugada ECG was never noticed. Conclusions— Ranolazine blocks I NaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients. Clinical Trial Registration— URL: https://clinicaltrials.gov ; Unique identifier: NCT01728025.

Modernized Classification of Cardiac Antiarrhythmic Drugs

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