pharmaceuticals

Review
Overview of Cardiac Arrhythmias and Treatment Strategies
John Kingma 1, * , Chantale Simard 2,3 and Benoît Drolet 2,3

1 Department of Medicine, Ferdinand Vandry Pavillon, 1050 Av. de la Médecine,

Québec City, QC G1V 0A6, Canada
2 Faculty of Pharmacy Ferdinand Vandry Pavillon, 1050 Av. de la Médecine,
Québec City, QC G1V 0A6, Canada; [email protected] (C.S.); [email protected] (B.D.)
3 Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval
2725 Chemin Sainte-Foy, Québec City, QC G1V 4G5, Canada
* Correspondence: [email protected]

Abstract: Maintenance of normal cardiac rhythm requires coordinated activity of ion channels and
transporters that allow well-ordered propagation of electrical impulses across the myocardium.
Disruptions in this orderly process provoke cardiac arrhythmias that may be lethal in some pa-
tients. Risk of common acquired arrhythmias is increased markedly when structural heart disease
caused by myocardial infarction (due to fibrotic scar formation) or left ventricular dysfunction is
present. Genetic polymorphisms influence structure or excitability of the myocardial substrate,
which increases vulnerability or risk of arrhythmias in patients. Similarly, genetic polymorphisms of
drug-metabolizing enzymes give rise to distinct subgroups within the population that affect specific
drug biotransformation reactions. Nonetheless, identification of triggers involved in initiation or
maintenance of cardiac arrhythmias remains a major challenge. Herein, we provide an overview of
knowledge regarding physiopathology of inherited and acquired cardiac arrhythmias along with a
summary of treatments (pharmacologic or non-pharmacologic) used to limit their effect on morbidity
and potential mortality. Improved understanding of molecular and cellular aspects of arrhythmogen-
esis and more epidemiologic studies (for a more accurate portrait of incidence and prevalence) are
crucial for development of novel treatments and for management of cardiac arrhythmias and their
consequences in patients, as their incidence is increasing worldwide.

Citation: Kingma, J.; Simard, C.; Keywords: cardiac arrhythmias; electrical remodeling; structural remodeling; pathophysiology;
Drolet, B. Overview of Cardiac
pharmacology; non-pharmacologic interventions
Arrhythmias and Treatment
Strategies. Pharmaceuticals 2023, 16,
844. https://doi.org/10.3390/
ph16060844
1. Introduction
Academic Editors: Norbert Nagy and
The original description of sudden cardiac death in seemingly healthy patients who
Norbert Jost
frequently experience severe fainting spells is attributed to Hippocrates [1]; various elec-
Received: 4 May 2023 trical diseases contribute to this situation, including long-QT syndrome, arrhythmogenic
Revised: 30 May 2023 right ventricular dysplasia or cardiomyopathy (Naxos disease), Brugada syndrome and
Accepted: 1 June 2023 hypertrophic cardiomyopathy [2]. It was not until the 19th century that Étienne-Jules Marey
Published: 6 June 2023 described the phenomenon of premature ventricular beats along with various aspects of
left and right ventricular contraction. Historical aspects of cardiac electrophysiology have
recently been discussed [2]. Greater understanding of the physiopathology of cardiac
arrhythmias at the subcellular and cellular levels, particularly the distinction between
Copyright: © 2023 by the authors.
ventricular arrhythmias and atrial fibrillation, is essential for development of novel phar-
Licensee MDPI, Basel, Switzerland.
macologic or non-pharmacologic interventions.
This article is an open access article
In clinical practice, atrial fibrillation (supraventricular tachyarrhythmia caused by
distributed under the terms and
uncoordinated atrial activation and atrial mechanical dysfunction) is a pervasive cardiac
conditions of the Creative Commons
arrhythmia, principally brought about by structural and electrophysiological alterations
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
in atrial tissues. It can be encountered in the absence of underlying heart disease but is
4.0/).
more frequently seen in connection with mitral valve disease, heart failure, ischemic heart

Pharmaceuticals 2023, 16, 844. https://doi.org/10.3390/ph16060844 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2023, 16, 844 2 of 20

disease and hypertension [3,4]. Early manifestations of atrial fibrillation can be controlled
with the use of pharmaceuticals; the overall goal of treatment being to improve survival,
reduce incidence of stroke, restore atrial functions, reverse ultrastructural remodeling and
improve symptoms.
While ventricular arrhythmias are, for the most part, catastrophic and require immedi-
ate attention, atrial fibrillation is usually asymptomatic, undetected and self-terminating.
However, over time, atrial fibrillation can evolve to a chronic stage (from paroxysmal),
which complicates clinical treatments. In other words, contributory mechanisms as well as
triggers change as the disease progresses [5,6]. The principal components that contribute
to various stages of atrial fibrillation progression have been characterized [7]. For exam-
ple, pronounced electrical and structural remodeling along with altered conduction and
refractoriness provide the substrate for atrial myocardium to become more vulnerable
to reentrant circuit formation [8], shortening of action potential and refractory period
duration [9–12], slowing of conduction and a lower threshold for alternans induction (a
crucial element for vulnerable substrate generation [13]. Ultrastructural alterations at the
level of the atrial cardiomyocyte membrane probably play a role in pathogenesis of atrial
fibrillation but additional structural and functional data are needed. All changes to atrial
tissue structure profoundly affect tissue conductivity, wave propagation and potential
for reentry.
Clinical and basic science studies have enabled development of clinical strategies to
improve quality of life in patients. Herein, we examine experimental and clinical advances
that are central to clinical treatment of cardiac arrhythmias. For this review, we searched
English-language clinical and basic science reports using the PubMed and Google Scholar
platforms with the search terms cardiac arrhythmias, ischemic heart disease, electrophysiol-
ogy, intrinsic cardiac nervous system, pharmacological treatments, implantable cardioverter
defibrillator, catheter ablation, ischemic preconditioning, and combinations thereof.

2. General Principles
Cardiac function relies on rhythmic contraction coordinated by specialized cardiac
pacemaker cells in mammalian hearts. A well-established electrical conduction system (i.e.,
sinoatrial and atrioventricular nodes, the His bundle, the right and left bundle branches,
the fascicles and the Purkinje fibers [14]) coordinates with cardiomyocytes and other cell
types to regulate cardiac function in an orderly fashion. Cardiac action potential requires
the highly coordinated action (i.e., opening/closing/inactivation) of plasma membrane
ion channel proteins; conduction depends on electrical coupling between different cell
types and is mediated by gap junctions [15]. In humans, the cardiac action potential
comprises five distinct phases (0–4) (cf. Larson and colleagues [16]): in phase 0, stimulation
from the sinoatrial node further brings the membrane potential of atrial myocytes to
threshold, thus opening voltage-activated sodium channels—sodium ions diffuse along
an electrochemical gradient (from the extracellular space, across the plasma membrane
and into the cell). The sodium current produces a positive feedback loop; most of the
available sodium currents remain in reserve. Rapid repolarization triggered by fast and
slow transient outward potassium currents (phase 1) is followed by a prolonged plateau
(due to equilibrium between inward (i.e., L-type calcium, sodium-calcium exchanger) and
outward (i.e., potassium—both delayed and inward rectifying) currents (phase 2). The
driving force for potassium efflux in this phase is high because of differences between
the membrane potential and the potassium Nernst potential [17]. In phase 3, calcium
currents are inactivated and outward potassium currents instigate repolarization such that
membrane potential is directed towards potassium equilibrium. In phase 4, membrane
potential returns to resting values after complete repolarization.
Mammalian cardiomyocytes express a diversity of voltage-gated ion channel pore-
forming subunits, which contribute to formation of inward and outward currents that
shape waveforms of action potentials and influence both automaticity and refractoriness.
The interplay between all of the ionic currents profoundly affects ventricular action poten-
Pharmaceuticals 2023, 16, 844 3 of 20

tial waveforms. Insights into these relationships have been provided through molecular
genetics studies.
In pacemaker cells (distinctive due to properties of automaticity) of the sinoatrial
and atrioventricular nodes, atria and the His–Purkinje systems, voltage and calcium de-
pendent mechanisms are involved [18]. Normally, the rate of discharge of the sinoatrial
node maintains heart rate between 60–100 beats per minute (bpm). Slower rates of dis-
charge occur in the atrioventricular node (40–60 bpm) or Purkinje system (20–40 bpm);
however, these slower rates are normally controlled by the dominant pacemaker, which
has a higher intrinsic rate of discharge. Greater automaticity results in a higher rate of
action potential discharge due to 1—negative shifts of the threshold potential; 2—a positive
shift in maximum diastolic potential; and 3—increased rate of phase 4 depolarization [19].
In the sinoatrial node, this increases heart rate (i.e., sinus tachycardia); the latter is either
physiologically caused by greater sympathetic tone or pathophysiologically caused by
hypovolemia, ischemia or disturbances in electrolytes. While alternating bradycardia and
tachycardia (as seen in patients with tachycardia–bradycardia syndrome) often occurs with
atrial fibrillation, the underlying mechanisms remain unclear. Further investigation of
different organizational manifestations of phase distribution during arrhythmias could im-
prove characterization of cardiac arrhythmias and provide additional mechanistic strategies
for modulating cardiac fibrillation in patients.
In the absence of a vulnerable myocardial substrate and an appropriate trigger, elec-
trical conduction in the heart is reasonably without incident. However, alteration of
cellular and electrophysiological properties (i.e., triggered activity, atypical automaticity, re-
entry) within the myocardium substantially increases the potential for cardiac arrhythmias.
Marked deceleration of early repolarization and acceleration of late repolarization caused
by changes in current expression result in atrial fibrillation; molecular changes that may
drive these outcomes include 1—augmented inward-rectified potassium current activity,
and 2—simultaneous reduction in L-type calcium current activity [5]. Remedial changes
include an increase in expression levels of the sodium–calcium exchanger and reductions
in rapidly activating outward currents and the fast component of the transient outward
potassium current [11,20,21]. The attendant shortened effective refractory period and more
negative resting membrane potential increase the window for reentrant excitation [22,23].
Electrical remodeling (i.e., altered functional expression of ionic currents) is associated
with ion channel gene mutations but is most important within the context of structural
myocardial disease. In the failing heart, electrical remodeling increases susceptibility to
both atrial and ventricular arrhythmias [24,25]. Distinct types of ion channel remodeling
produce differing types of atrial fibrillation; for instance, tachycardia-induced remodeling
involves shortening of atrial refractoriness, while in the aging or failing heart, fibrosis slows
conduction velocity, thus prolonging atrial refractoriness. Cardiac wavelength is the physi-
cal distance traveled by an electrical impulse within a refractory period; reentry depends
on the wavelength being shorter than the total length of the reentrant pathway [26]. A mul-
tiplicity of factors, including action potential shortening, induction of depolarizing inward
currents and impaired intracellular conduction, contribute to genesis of arrhythmias after
acute cardiac ischemia [27]. Acute ischemia increases intracellular resistance and shortens
action potential duration consequent to gap junction uncoupling [28]. Persistent cellular
uncoupling amplifies spatial differences in repolarization, thereby promoting reentry. Sus-
ceptibility to arrhythmias (i.e., ranging from premature ventricular beats to fibrillation)
occurs almost immediately after restoration of blood flow to ischemic myocardium [29,30].
Experimental models to evaluate cardiac cell electrophysiology and changes in the
time and voltage dependence as well as the time course of ionic currents that underlie
the action potential have been available since they were initially reported by Professor
Noble in 1962 [31] (cf. in-depth review by Vagos et al. [20]). More recently, in silico (i.e.,
computational models) drug-screening studies use a mechanistic approach whereby the
effects of drug binding are simulated by alteration of gating kinetics of specific ion channels.
Using a population models approach [32,33] (as opposed to the single averaged model
Pharmaceuticals 2023, 16, 844 4 of 20

approach), studies in cardiomyocytes added natural variability to provide more robust

and reliable arrhythmia risk markers and metrics [34]. Computational models have also
been developed to assess molecular mechanisms that give rise to various aspects of atrial
fibrillation, such as spatially discordant alternans [35], which appears to immediately
precede atrial fibrillation in patients [13]; contributing mechanisms have not been resolved,
but instability in cellular Ca2+ cycling may be important [36–38].

2.1. Genetics
Most cardiac arrhythmias occur as a result of structural myocardial disease, but they
also occur in response to various genetic and environmental risk factors and altered epige-
netic regulation [39]. The latter are classified by location of origin, polymorphic ventricu-
lar tachycardia dominated by primary hereditary arrhythmia syndrome and ventricular
fibrillation [40,41].
Increasing interest in determining genes that are responsible for causing hereditary
arrhythmogenesis is emerging (cf. recent state-of-the-art review by Wang and Tu [42]);
numerous mutations of ion channels that configure the cardiac action potential have been
determined. Other mutations are also known to reside in gene coding proteins with
different biological functions, such as cytoskeletal architecture, calcium handling, sodium
transport and cytokine signaling [43–45]. Defects in a host of cytoskeleton proteins (desmin,
lamin, titin, filamin, etc.) markedly affect structural integrity and mechanotransduction in
cardiomyocytes (cf. review paper by Austin and colleagues [46]). Similarly, mutations in
genes that regulate calcium homeostasis (i.e., phospholamban, SERCA2, ryanodine receptor,
etc.) can potentially provoke arrhythmogenesis. Genome-wide association analyses are
particularly helpful and have revealed a large number of genetic risk variants (mostly
located within intergenic/intronic regions) associated with atrial fibrillation [47].
Multiple microRNAs play a fundamental role in regulating key components (i.e.,
electrical, structural remodeling) of electrical conduction; impairment of any of these
components can lead to development of atrial fibrillation (cf. review article [48]). Long non-
coding RNAs may also be involved in modulating fibrosis, ion channel function or energy
metabolism [49–51]. DNA methylation and histone modification might also link genetic
variations with predisposition to atrial fibrillation, but more data are needed. Emerging data
intimate that histone deacetylases linked to gene silencing could affect post-transcriptional
regulation of specific proteins (i.e., cytoskeletal or conductive) in cardiomyocytes and
thereby contribute to atrial fibrillation [52–54]. Presently, major gaps exist with regard to
knowledge of molecular alterations and pathogenesis of cardiac arrhythmias. Different
atrial fibrillation risk variants could also act additively in response to epigenetic factors [48].
Epigenetics (changes in gene expression that occur without changes in DNA
sequence [55]) examines potential links between external risk factors and internal ge-
netic machineries along with mechanisms to preserve selected gene activity states [56].
Diverse epigenetic processes, such as expression of non-coding RNA molecules, DNA
methylation and histone modification, affect expression of genes that produce significant
alterations in cellular structure and function [57]. Epigenetic mechanisms can be acquired
or inherited, but their actual role in regulation of atrial fibrillation is unclear.

2.2. Myocardial Ischemia

Acute obstruction of a coronary vessel produces profound pathological changes in
cardiomyocytes (within the area of no blood flow or anatomic area at risk) due to abrupt
stoppage of biochemical and metabolic pathways. Reduced oxygen delivery halts oxida-
tive phosphorylation, depletion of intracellular energy phosphate stores and inhibition
of myocyte contractile function. Ischemic heart disease is a major contributor to cardiac
arrhythmias, which can be life threatening in patients [58]. Ischemic injury causes struc-
tural damage as well as electrical instability (due to excessive sympathoexcitation and
attenuation of parasympathetic tone) that predisposes to arrhythmias [29,59]. In addition,
membrane potential, speed of depolarization and refractory period within ischemic my-
Pharmaceuticals 2023, 16, 844 5 of 20

ocardium and between ischemic and non-ischemic regions are significantly modulated.
During acute myocardial infarction, automaticity within the atrioventricular node increases
to produce focal atrial tachycardia [60]. Parasystole (i.e., an ectopic pacemaker that dis-
charges at a constant rate and competes with the sinus node—the principal pacemaker of
the heart) caused by ischemia or infarction prevents conduction of action potentials to the
latent pacemaker; a parasystolic focus occurs when conduction to the ectopic pacemaker
and exit conduction are compromised [61,62]. Tissue fibrosis caused by ischemia depresses
conduction velocity and is accompanied by directional differences in wave front propaga-
tion; unidirectional block, wave break and reentry are commonly associated with patchy
fibrosis throughout the myocardium [63,64].
Timely opening of an infarct-related artery is essential for the salvage of viable car-
diomyocytes in the anatomic area at risk. While restoration of blood flow to the vascular
bed of an infarct-related artery using percutaneous coronary interventions or thrombolytic
agents delays necrosis, this may be a mixed blessing as further cardiomyocyte damage may
occur to reversibly injured myocytes in the area at risk (i.e., reperfusion injury) [65]. A lethal
consequence of reflow after regional myocardial ischemia is the occurrence of reperfusion-
induced arrhythmias [30]. Multiple contributory factors, including oxidative stress, calcium
influx, altered cellular pH, the opening of a mitochondrial permeability transition pore,
etc., are likely responsible [66–68]. Reperfusion of the ischemia- or infarct-related coronary
vessel(s) restores most parameters; for example, amplitude of depolarization is improved,
but synchronicity and refractory period are not [69]. The severity of reperfusion-induced
arrhythmias depends on the duration of ischemia. With brief (<3 min) or prolonged
(>60 min) ischemia, the occurrence of arrhythmias in animal models is relatively low [29];
between these durations of ischemia, the incidence of malignant reperfusion arrhythmias
increases markedly.
Structural/electrical remodeling, altered hemodynamic loads and altered neurohor-
monal signaling occur during ischemia/reperfusion. They markedly change ion channel
function, intracellular ion handling and communication. The type of remodeling is depen-
dent on the strength and duration of the stressor (i.e., electrical—tachycardia; mechanical—
volume or pressure overload) [70]. The presence of fibrotic tissue significantly modulates
myocardial electrophysiological properties and is a key promoter of arrhythmia progres-
sion, due to impaired conduction through the myocardium (i.e., a conduction mismatch
between a narrow island of tissue and a larger myocardial mass due to blockage of voltage
necessary to activate the distal myocardium [71]), induction of impedance mismatches
and conduction discontinuity, along with unidirectional blocks and reentry substrates [72].
Proliferation of fibroblasts, which act as current sources or sinks during excitation in
affected myocardium, is linked to abnormal automaticity. Consequently, therapeutic ap-
proaches that prevent fibroblast proliferation, secretion and connexin expression could be
helpful [73]. Initiation and maintenance of atrial fibrillation is attributed to 1—a single
ectopic focus (myocytes located within pulmonary veins) that triggers or maintains atrial
tachycardia, fibrillation or electrophysiological remodeling, resulting in continuous atrial
fibrillation (i.e., atrial fibrillation begets atrial fibrillation [74]); 2—reentrant circuits that
activate atria with fibrillatory conduction, resulting in irregular rhythms; and 3—both ec-
topic activation and single reentry circuits that initiate multiple wavelets (due to numerous
distinct electrical circuits being activated within the atria) [75]. The multiple wavelet reentry
hypothesis may be the final common pathway for atrial fibrillation. In the structurally
compromised heart, prolongation of action potential duration and alteration of action
potential dynamics involve downregulation of repolarizing K+ currents (i.e., Ito , IKr , IKs ,
IK1 ) and altered handling of intracellular calcium [24]. An important electrophysiological
effect of K+ current downregulation is a reduced repolarization reserve; as a result, ventric-
ular myocardium is more susceptible to early afterdepolarizations and functional reentry.
Repolarization reserve was first introduced in 1998 [76]; this concept suggests that the com-
plexity of repolarization includes some redundancy, therefore loss of a specific component
Pharmaceuticals 2023, 16, 844 6 of 20

(i.e., IKr ) will not ordinarily lead to failure of repolarization (cf. Varro and Baczko [77] for
further details).
Altered ventricular mechanics and heightened electrical instability in failing my-
ocardium are triggered by irregularities in intracellular Ca2+ handling. Mechanisms such
as Ca2+ -mediated inactivation of L-type Ca2+ channels, activation of Ca2+ -sensitive trans-
porters and the Na+ -Ca2+ exchanger all link intracellular Ca2+ homeostasis and ventricular
action potentials. Alterations in Na+ currents and reduced current density also impact
conduction in tissues that are adjacent to non-infarcted myocardium in the non-ischemic
risk zone [78–80]. The speed of wave-front necrosis (i.e., progression of cellular injury from
endocardium to epicardial layers of the myocardial wall of the left ventricle) is signifi-
cantly affected by location, density and expression of gap junction channel proteins [81,82];
abnormal conduction is due, in part, to loss or redistribution of connexin 43 (i.e., a princi-
pal gap junction protein) from the intercalated disk to the lateral cell border in ischemic
myocardium [83]. Reduced coupling between normal and affected cardiomyocytes has
an effect on action potential duration, predisposing cells to conduction block and reen-
trant excitation [84,85]. The link between atrial fibrillation, elevated connexin 43 expres-
sion and modified anisotropy (i.e., due to altered distribution of gap junctions) has been
documented [86,87]. In animal studies, protection against atrial fibrillation is associated
with reduced connexin 43 expression levels [88] or altered distribution of the gap junction
complex [89].

2.3. Inflammation
The contribution of inflammation as a cause of cardiac arrhythmias is largely over-
looked; however, its role in the development of atrial fibrillation is increasingly apparent,
as evidenced by the observed acute increase in inflammatory proteins [90–92] in patients.
In fact, cardiac or systemic inflammation occurs normally as part of the body’s non-specific
response to injury [93]. In a structurally normal heart, acute inflammation may provoke
supraventricular ectopic beats; however, a higher incidence of malignant arrhythmias
without sudden cardiac death is observed in patients with febrile illness [94]. In failing
hearts, electrophysiological remodeling (i.e., ion channel expression, ionic homeostasis,
etc.) contributes to alteration of action potential duration, long-QT syndrome, Torsade
de Pointes and atrioventricular block and other repolarization abnormalities that can
further impact myocardial instability [95]. Inflammatory cytokines induce various arrhyth-
mogenic syndromes via a host of mechanisms that cause inflammatory channelopathies,
altered ion homeostasis or ultrastructural remodeling. The anti-inflammatory actions of
statins on atrial end-refractory period (i.e., the interval from depolarization to the recovery
of excitability) and atrial fibrillation duration in animal and human studies have been
reported [96,97].
An unanticipated emergence of cardiac arrhythmias in patients with COVID-19 has
been described in recent studies [98–100]; potentially related to inflammatory cytokines (i.e.,
TNF, IL-1, IL-6, etc.) that have a direct influence on cardiac function and indirect systemic
changes [95]. In patients with severe COVID-19, a lower incidence of cardiovascular-related
death following treatment with glucocorticoids or IL-6 receptor antagonist treatment has
been reported [101].

2.4. Diet and Metabolic Disorders

A pathological link between dietary disorders (i.e., dyslipidemia, obesity, Type 2
diabetes, insulin resistance, etc.) and cardiac dysfunction has been suggested. Under
normal circumstances, the heart uses free fatty acids as an energy source via a regulated
equilibrium between cardiac lipid uptake and oxidation. Metabolic disorders produce a
situation where lipid levels exceed storage capacity of adipocytes, which then leads to
intracellular accumulation of lipid droplets (with attendant disruption of cardiac function).
Myocardial lipid accumulation generally impairs fatty acid metabolism and inflammation
and increases vulnerability to sustained or even fatal arrhythmias [102–104]; however,
Pharmaceuticals 2023, 16, 844 7 of 20

excessive accumulation of free fatty acids can also augment inflammation responses [105].
The interplay between free fatty acid toxicity and activation of intracellular signaling
pathways leads to ion channel remodeling, with subsequent effects on cardiac electrical
activity and abnormal conduction [106–108]. Protection afforded by polyunsaturated fatty
acids via actions on channel gating and membrane properties, including modulation of
cardiac connexins, has been discussed [88,109,110]. These findings support the notion of a
relationship between diet, inflammation and arrhythmogenesis.

3. Pharmacotherapy
The Vaughan Williams classification system (cf. Table 1) is widely used to classify the
plethora of anti-arrhythmic drugs and is based on ionic channel involvement and effects on
action potential, sinus node function and atrioventricular conduction (see the recent review
by Larson et al. [16]). Class I medications have a wide variety of effects that target blockade
of sodium channels; these drugs block the rapid inward sodium current, thereby cardiac
depolarization and conduction, along with prolongation of repolarization (via blockade
of delayed rectifier K+ channels). They also affect action potential and effective refractory
period duration and thereby influence automaticity. Class II medications (i.e., beta blockers)
act by blunting sympathetic activity, resulting in a reduced rate of the initial depolarization
of the action potential, which mitigates automaticity and conduction velocity [111]. The
use of beta-blockers for treatment of arrhythmias may reduce the risk of sudden death
in patients [112]; however, other studies refute this claim [113,114]. On the other hand,
combination therapy, with implantable cardiac defibrillators and beta-blockade medica-
tions, provides significant benefit in clinical studies [115–117]. Class III medications (i.e.,
potassium channel blockers) act mostly by blocking the delayed rectifier potassium channel,
thereby prolonging repolarization [118–120]. Class IV medications (i.e., calcium channel
blockers) act primarily at the level of the atrioventricular node by blocking slow inward
Ca currents; this results in a prolongation of the effective refractory period while having a
minimal effect on cardiomyocytes or the His–Purkinje system [121,122]. Although calcium
channel blockers are of limited usefulness for most forms of ventricular tachycardia, they
are considered a useful adjunctive therapy for catecholaminergic polymorphic ventric-
ular tachycardia (inherited tachycardia in structurally normal hearts during increased
sympathetic activity [123]) and idiopathic left ventricular tachycardia [16].

Table 1. Vaughan Williams classification of antiarrhythmic drugs.

Class Drugs
Class I: Sodium Channel Blockers
Ia Disopyramide, Procainamide, Quinidine
Ib Lidocaine, Mexiletine
Ic Flecainide, Propafenone
Acebutolol, Atenolol, Bisoprolol, Carvedilol,
Class II: Beta-blockers
Esmolol, Metoprolol, Nadolol, Propranolol
Amiodarone, Bretylium, Dofetilide,
Class III: Potassium Channel Blockers Dronedarone, Ibutilide, Sotalol, Vernakalant
(not available in USA)
Class IV: Calcium Channel Blockers Diltiazem, Verapamil
Others Adenosine, Atropine, Digoxin

Some pharmaceuticals outside the Vaughan Williams classification system are notable
for their anti-arrhythmic actions. For example, ranolazine, primarily used as an antianginal
medication with its late sodium channel (INa-L )-blocking effect, also acts in a manner similar
to amiodarone (i.e., blockade of inward depolarizing and outward repolarizing currents
that affect sodium, potassium and calcium currents to prolong action potential duration)
Pharmaceuticals 2023, 16, 844 8 of 20

to reduce recurrence of arrhythmias [124,125], in addition to its role in controlling atrial

fibrillation. The principal antiarrhythmic actions of ranolazine involve the blockade of
peak INa , which reduces excitability and leads to prolongation of the end-refractory period
(causing reduced activation of the atria) [126]. However, the role of late INa inhibition
by ranolazine in the management of AF has not been established. Several clinical trials
(RAID, MERLIN-TIMI, RESTYLE-HCM) have reported variable findings with respect to
risk reduction for arrhythmias with ranolazine [125,127,128].
Another antianginal drug, ivabradine (mixed sodium–potassium current blocker),
unlike beta-blockers, reduces heart rate without affecting other aspects of cardiac func-
tion, such as inotropy [129]. That being said, further information is necessary since there
is a greater relative risk of atrial fibrillation (related to symptomatic bradycardia) in pa-
tients [130–132]. Adenosine, which acts on specialized conduction tissues in the sinoa-
trial and atrioventricular nodes, reduces automaticity to effectively limit repetitive and
paroxysmal monomorphic ventricular tachycardia (i.e., adenosine-sensitive ventricular
tachycardia) [133–135]. Digoxin produces both mechanical and electrophysiological effects
on the heart via inhibition of Na+ /K+ ATPase (raises intracellular calcium) and enhanced
contractility (via increased vagal tone at the level of the atrioventricular node), thereby low-
ering conduction velocity and increasing the effective refractory period [16]. However, use
of digoxin in patients has been curbed (except in advanced heart failure and refractory atrial
fibrillation) due to a potential increased risk of arrhythmia-mediated mortality [136,137].
While clinical use of pharmacological agents to limit cardiac arrhythmias is the
norm, significant cardiac and extracardiac (i.e., neurohumoral activation) side effects have
also been described, the most important being their potential proarrhythmic properties
in patients with structural heart disease [138]. While clinical trials examining the effi-
cacy of anti-arrhythmic agents on suppression of arrhythmias have provided important
findings, some (Cardiac Arrhythmia Suppression Trials I and II) were unable to demon-
strate significant protection in patients with serious arrhythmias and were prematurely
terminated [139]. Greater understanding of the underlying mechanisms for pathogenesis of
arrhythmias at the molecular, cellular and tissue levels is crucial for development of specific
pharmacotherapeutic targets, in combination with, or without, other non-pharmacologic
interventions.

4. Non-Pharmacologic Interventions
First-order treatment against cardiac arrhythmias in patients is principally accom-
plished using antiarrhythmic drugs. However, evidence of the overall efficacy of phar-
macotherapy is incomplete. This has spurred development of interventions such as im-
plantable electronic pacemakers, cardioverter defibrillators and catheter ablation.

4.1. Implantable Devices

Cardiac pacing (i.e., electrical stimulation to modulate cardiac mechanical activity)
was introduced clinically in the 1930s (cf. Figure 1). Electronic pacemaker devices (i.e.,
unipolar, bipolar) that deliver an electrical pulse sufficient to depolarize myocardium
(i.e., stimulation threshold) are standard therapy for symptomatic bradycardia-related
symptoms caused by atrioventricular node block or sinus node dysfunction, and severe
left ventricular dysfunction [140]. Optimization of parameters such as pulse amplitude
and duration is essential to effectively treat symptoms (delayed/absent activation of entire
ventricle) in patients [141,142]. While significant advances have been made with this
technology, major shortcomings (cost, infection, hemorrhage, lead failure, cardiopulmonary
collapse, etc.) have led to a paradigm shift regarding overall use. New battery-less devices
are presently under development and should provide benefit for cardiac resynchronization
therapy in heart failure patients. Finally, gene-therapy-based manipulation of ionic currents
(via delivery of nucleic acid sequences into target cells or tissues), implantation of biological
pacemakers that modify cardiomyocytes to provide automaticity or stem cell treatments
that add pacemaker syncytia to the heart are presently being investigated [143–146]. Greater
 ogy, major shortcomings (cost, infection, hemorrhage, lead failure, cardiopulmonary col-
lapse, etc.) have led to a paradigm shift regarding overall use. New battery-less devices
are presently under development and should provide benefit for cardiac resynchroniza-
tion therapy in heart failure patients. Finally, gene-therapy-based manipulation of ionic
currents (via delivery of nucleic acid sequences into target cells or tissues), implantation
Pharmaceuticals 2023, 16, 844 9 of 20
of biological pacemakers that modify cardiomyocytes to provide automaticity or stem cell
treatments that add pacemaker syncytia to the heart are presently being investigated [143–
146]. Greater understanding of mechanisms that regulate gene expression and coupling
understanding
between donor of mechanisms
and host cells isthat regulate
essential genebiological
before expressionpacemakers
and coupling between
become donor
meaning-
and host cells is essential before biological
ful therapies for conduction system disorders. pacemakers become meaningful therapies for
conduction system disorders.

Non-pharmacologic Interventions

Implantable devices Catheter ablation

Figure 1. Non-pharmacologic interventions: implantable devices and catheter ablation.

Figure 1. Non-pharmacologic interventions: implantable devices and catheter ablation.
Implantable cardioverter defibrillators were initially used more than 30 years ago in
Implantable
patients recovering cardioverter
from near-fataldefibrillators
ventricularwere initially used
fibrillation more than
and syncope 30 documented
with years ago in
patients recovering from near-fatal ventricular fibrillation and syncope
sustained ventricular tachycardia, with or without compromised left ventricular ejection with documented
sustained
fraction ventricular
(<40%). tachycardia,
Survival, with
after a two or without
year follow-up compromised
period, was left ventricular
significantly ejection
greater in
fraction (<40%). Survival, after a two year follow-up period, was significantly
these patients compared to pharmacologic treatment [147]. Smaller randomized clinical tri- greater in
these patients compared to pharmacologic treatment [147]. Smaller randomized
als examining the efficacy of these devices post-implant reported that overall survival [148] clinical
trialsrisk
and examining
of adversetheoutcomes
efficacy [149]
of these
weredevices post-implant
not enhanced. reported
Although that overall
cardioverter survival
defibrillators
adequately terminate arrhythmias, they cannot prevent their occurrence [17]. Efficacy defib-
[148] and risk of adverse outcomes [149] were not enhanced. Although cardioverter of the
rillators adequately
implantable terminate
cardioverter arrhythmias,
defibrillator requiresthey
thecannot
capacityprevent their occurrence
to properly [17]. Ef-
detect arrhythmias
ficacy
and to of the implantable
deliver cardioverter
the anti-tachycardia defibrillator
pacing requires the
or shock required capacity to properly
for cardioversion detect
[150]. Shocks
arrhythmias and to deliver the anti-tachycardia pacing or shock required
can occur frequently early after implantation and can be painful, thus reducing quality of for cardiover-
sion(i.e.,
life [150]. Shocks can
decreased occurfunction
physical frequentlyandearly afterwell-being)
mental implantation for and can be
patients painful,Since
[151,152]. thus
reducing
the qualityofofthese
publication life (i.e., decreased
findings, physical
questions havefunction
arisen and
withmental
regardwell-being) for pa-
to overall efficacy
tients
of [151,152]. cardioverter
implantable Since the publication of these
devices for findings,
secondary questions
prevention inhave arisen
patients with
with regard
multiple
to overall efficacy of implantable cardioverter devices for secondary prevention
comorbidities that have survived a cardiac arrest [153]. Combined treatment with pharma- in patients
cotherapy in addition to an implantable cardioverter device for management of arrhythmias
in patients has recently been shown useful to reduce the defibrillation threshold (i.e., the
energy required for defibrillation and restoration of normal sinus rhythm) needed for
cardioversion [154]. Future research is warranted to evaluate potential protection us-
ing combined pharmacologic and non-pharmacologic treatments for cardiac arrhythmias
in patients.

4.2. Catheter Ablation

Retrospective clinical findings suggest that ablation is considerably more effective
than conventional pharmacotherapy for treatment of cardiac arrhythmias [155,156]. Re-
cent guidelines suggest that catheter ablation be used for recurrent paroxysmal atrial
fibrillation [157], and several clinical trials have documented the superiority of catheter
ablation in patients refractory to pharmacotherapy [158,159].
Pharmaceuticals 2023, 16, 844 10 of 20

Extrinsic (vagus nerve) and intrinsic (network of intracardiac ganglia and intercon-
necting neurons) components comprise the cardiac autonomic nervous system, which
regulates heart rate and cardiac output in response to varying physiologic states [160].
The extrinsic cardiac system contains fibers that connect the heart to the nervous system
and the intrinsic cardiac system contains autonomic nerve fibers within the pericardial
sac [161]. Cardiac electrophysiology and arrhythmogenesis are significantly impacted by
dysfunction of the autonomic nervous system due to the marked diversity in autonomic
triggers [162,163]. Identification of these triggers has led to testing of various interventions
(i.e., neural ablation or stimulation) that could modulate autonomic activities involved in
arrhythmogenesis. Autonomic nervous system dysfunction plays a major role in induction
and maintenance of atrial and ventricular arrhythmogenesis [164]; increased sympathetic
drive impairs the detrimental effects of ischemia and underlying rhythm disturbances [165].
Catheter ablation of atrial fibrillation is a widely used therapeutic modality in symptomatic
patients with irrepressible or persistent atrial fibrillation that are refractory or intolerant to
antiarrhythmic drugs. Ablation involves point-by-point lesions (applied using radiofre-
quency or cryotherapy) that encircle the ipsilateral ostia of the pulmonary veins [166] or
other target areas. Ganglionated plexi (i.e., localized neural clusters of intrinsic cardiac
ganglia that contain local circuits, parasympathetic neurons and sympathetic afferent and
efferent neurons [167]) embedded in adipose tissue on the posterior regions of the atria and
the posterior–superior aspect of the ventricles are also targeted [168,169]; however, further
validation of ganglionated plexus ablation for treatment of atrial fibrillation is needed.
Some collateral damage, including cardiac tamponade, stroke, atrio-esophageal fistula,
pulmonary vein stenosis, etc., constitutes a significant drawback to more widespread use of
these techniques [166,170]. Nonetheless, considerable immediate and long-term benefit to
arrhythmia patients, with regard to recurrence of arrhythmias and quality of life, has been
reported with ablation interventions [155,158,171–173]. Difficulties associated with this
type of intervention include limited resolution of mapping technologies; however, the use
of more widely available electroanatomic mapping, magnetic resonance or tomographic
cardiac images has helped to improve procedural outcomes [174,175]. A further compli-
cation includes the potential for recovery of conduction across previously ablated tissue,
which ultimately results in a return of arrhythmias [7]. Controversies surrounding catheter
ablation for cardiac arrhythmias have been discussed in a review paper by O’Neill and
co-workers [3].

4.3. Ischemic Conditioning

Potent, non-pharmacologic protective interventions for lethal ischemia–reperfusion-
injury-mediated arrhythmias have emerged in experimental and clinical studies. Ischemic
conditioning consists of brief episodes of repeated arterial occlusion/reperfusion carried
out prior to a longer episode of arterial occlusion [176] and has been reported to 1—protect
against cellular necrosis; 2—preserve post-ischemic cardiac function; and 3—decrease
the incidence of cardiac arrhythmias [177–179]. Whether antiarrhythmic protection by
ischemic conditioning is related to overall protection afforded against tissue injury has not
been established.
Despite the many thousands of published studies that report the considerable benefits
of ischemic conditioning against ischemic injury, translation to clinical practice remains a
particular challenge, in part due to a limited time frame during which potential protective
mechanisms can be solicited as well as the random nature of acute myocardial disease (i.e.,
ischemia, infarction, etc.). Whether ischemic conditioning can abolish or merely delay the
onset of ischemia or reperfusion-induced cardiac arrhythmias remains to be established—
the same question persists with regard to structural myocardial damage post-ischemia.
Nonetheless, the use of post- or remote ischemic conditioning (cf. Figure 2) in patients
appears to be promising with regard to arrhythmogenesis since the intervention could
be incorporated into current treatment algorithms for primary percutaneous coronary
interventions. Theoretically, myocardium subject to ischemic conditioning (after a cardiac
 disease (i.e., ischemia, infarction, etc.). Whether ischemic conditioning can abolish or
merely delay the onset of ischemia or reperfusion-induced cardiac arrhythmias remains
to be established—the same question persists with regard to structural myocardial dam-
age post-ischemia. Nonetheless, the use of post- or remote ischemic conditioning (cf. Fig-
Pharmaceuticals 2023, 16, 844
ure 2) in patients appears to be promising with regard to arrhythmogenesis since the in-
11 of 20
tervention could be incorporated into current treatment algorithms for primary percuta-
neous coronary interventions. Theoretically, myocardium subject to ischemic condition-
ing (after a cardiac event) should provide a substrate where ischemic myocardium is able
event)
to moreshould
readilyprovide a substrate
adapt to whereeffects
the deleterious ischemic myocardium is Spannbauer
of re-oxygenation. able to moreandreadily
col-
adapt to the deleterious effects of re-oxygenation. Spannbauer and colleagues
leagues recently conducted a small study in a porcine preparation of acute myocardialrecently
conducted a small study in a porcine preparation of acute myocardial infarction where
infarction where they compared two ischemic conditioning strategies (classic ischemic
they compared two ischemic conditioning strategies (classic ischemic preconditioning
preconditioning and post-ischemic conditioning) on cardiac arrhythmias [69]; their find-
and post-ischemic conditioning) on cardiac arrhythmias [69]; their findings showed that
ings showed that post-ischemic conditioning (i.e., after an ischemic event) exhibited sig-
post-ischemic conditioning (i.e., after an ischemic event) exhibited significant antiarrhyth-
nificant antiarrhythmic properties (compared to ischemic preconditioning—carried out
mic properties (compared to ischemic preconditioning—carried out prior to an ischemic
prior to an ischemic event). In addition, they reported a significant downregulation of
event). In addition, they reported a significant downregulation of microRNAs (related to
microRNAs (related to cardiac conduction).
cardiac conduction).

Ischemic conditioning

Postconditioning Ischemia-Reperfusion Injury Remote conditioning

Cardioprotection?

Figure 2.2.Non-pharmacologic
Figure Non-pharmacologicinterventions: ischemic
interventions: conditioning;
ischemic post-conditioning
conditioning; by angioplasty
post-conditioning by angio-
(left panel) and remote (or distant) organ conditioning (right panel). The middle panel
plasty (left panel) and remote (or distant) organ conditioning (right panel). The middle shows site
panel
of myocardial ischemia that could be affected by ischemic conditioning treatment.
shows site of myocardial ischemia that could be affected by ischemic conditioning treatment.

A
A more
more relevant
relevant intervention
intervention with
with clinical
clinical potential,
potential, remote
remote ischemic
ischemic conditioning
conditioning
(i.e., brief, repetitive ischemia–reperfusion cycles in an organ or
(i.e., brief, repetitive ischemia–reperfusion cycles in an organ or limblimb distant from
distant thethe
from target
tar-
organ), has been used to limit myocardial injury during cardiac surgery but might
get organ), has been used to limit myocardial injury during cardiac surgery but might also also be
applied to limit arrhythmogenesis. To date, findings for this intervention in clinical
be applied to limit arrhythmogenesis. To date, findings for this intervention in clinical studies
remain ambiguous. Significant protection against new onset atrial fibrillation has been
reported in patients undergoing cardiac surgery [180,181]; however, other large clinical
trials have reported no benefits [182–185]. A recent meta-analysis of a dozen randomized
control clinical studies of more than 5000 patients concluded no benefit to patients with
regard to new onset atrial fibrillation [186]; no other types of arrhythmias were investigated.
In experimental studies, treatment with remote ischemic conditioning also appears to
provide limited protection against ischemia-induced arrhythmias [187–190]. Differences
with regard to anesthetic regimes, ischemic conditioning protocols, animal species, etc.,
may be partly responsible for the variability in outcomes.

5. Perspectives
The prevalence of cardiac arrhythmias and their consequences is increasing worldwide
and may be explained by improved diagnostic tools and detection strategies available to
clinicians and health care professionals. Worldwide projections are that cardiac arrhyth-
mias affect almost two percent of the global population and are associated with substantial
socioeconomic burden. This review article presents recent findings regarding the patho-
Pharmaceuticals 2023, 16, 844 12 of 20

genesis of cardiac arrhythmias as well as different strategies for their clinical management.
Treatment for arrhythmia depends on the underlying cause. Some cases require medication,
while others require more invasive procedures such as electrical cardioversion, catheter
ablation or implantation of a pacemaker or defibrillator. The ultimate goal of treatment is to
restore normal sinus rhythm, so it is imperative that the processes associated with electrical
and structural modeling that perpetuate cardiac arrhythmias are reversed. However, it is
increasingly clear that pharmaceuticals alone are limited with regard to efficacy for treat-
ment of cardiac arrhythmias. As a result, considerable efforts are underway to find relevant
alternatives; combined therapy using pharmacologic and non-pharmacologic interventions
should not be excluded.
The identification of risk factors responsible for the pathogenesis of cardiac arrhyth-
mias needs to be addressed. Increasing focus on sex and gender differences is also necessary
with regard to the pathogenesis of cardiac arrhythmias [191–193]; important electrophys-
iologic differences between men and women in an aging population have long been de-
scribed. Present data indicate significant sex and gender differences regarding the incidence
and importance of risk factors and etiology of cardiac arrhythmias. Finally, awareness
surrounding physiological differences as well as etiology of the differences is un-clear. How-
ever, awareness of sex and gender aspects may have important implications for clinical
management of all patients with cardiac arrhythmias. What mechanisms, genetic or other-
wise, need to be studied to guide future treatment stratagems for primary and secondary
prevention of cardiac arrhythmias? Future translational and epidemiologic studies are
necessary to help identify novel targets for clinical (and possibly personalized) treatment of
cardiac arrhythmias.

Author Contributions: Original draft preparation, writing, reviewing and editing, J.K., B.D. and C.S.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The authors thank Denys Simard for helpful commentary and suggestions
during the revision of this paper.
Conflicts of Interest: The authors declare no conflict of interest.

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