(Circulation. 2000;102:IV-52.)
© 2000 American Heart Association, Inc.
Special Anniversary Issue |
What Have We Learned About Cardiac Arrhythmias?
From the Krannert Institute of Cardiology (D.P.Z.), Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Ind, and the Department of Cardiology (H.J.J.W.), Academic Hospital Maastricht and the Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202.
Key Words: ablation • arrhythmia • death, sudden • electrophysiology • pacemakers
No subspecialty in cardiology has undergone a more radical transformation in the last half century than has clinical cardiac electrophysiology. From the creation of the coronary care unit (CCU), with its concept of intensive monitoring of patients who have cardiac arrhythmias, to understanding the genetics of ion channel disturbances responsible for inherited cardiac arrhythmias, clinical cardiac electrophysiology has evolved into an established discipline credited with improving and saving hundreds of thousands of lives. In this review, we will highlight the top 10 significant advances responsible for this remarkable transformation.
Clinical Concepts
Ambulatory ECG
Recording the ECG in the ambulatory individual provided
the ability for the first time to obtain online information in an
active individual. Begun by Holter and
Gengerelli1 in 1949,
the initial device weighed 85 pounds and was strapped to the back. The
most modern version is implanted subcutaneously and can monitor the
cardiac rhythm for long time
periods.2 Ambulatory
ECG has led to many new insights, including an understanding of the
mechanisms of sudden cardiac death, causes of syncope, and the concept
of painless ischemia. All implantable pacemakers and
cardioverter/defibrillators (ICDs) have the ability to record the
cardiac rhythm, which is a useful adjunct to decision
making.
The CCU
A major step forward in reducing death from myocardial
infarction was the introduction of the
CCU,3 where
continuous monitoring of cardiac rhythm and hemodynamic status allowed
early recognition and correction of life-threatening
complications.4
Closed-chest cardiac massage and defibrillation became important
life-saving measures, and the value of the well-trained nurse in this
milieu became clear. The CCU also taught us to develop short- and
long-term risk profiles of the patient, based on ECG, hemodynamic, and
enzymatic findings. The concept of warning arrhythmias emerged along
with the use of prophylactic lidocaine
administration.5
Neither stood the test of
time.6 7
The CCU was also the testing site for appraising the value of
pharmacological and nonpharmacological interventions in reducing
infarct size with ß-blocking agents, thrombolytic agents, or primary
angioplasty. Reducing infarct size has also helped to lower the
incidence of postinfarction ventricular arrhythmias. The CCU became the
center of modern cardiology, the place where rapid, informed decision
making for diagnosis and treatment determined the future of the cardiac
patient.
Sudden Cardiac Death and Out-of-Hospital
Resuscitation
As recently
reviewed,8 sudden,
unexpected cardiac death continues to be a very common mode of death.
In fact, 20% of all deaths are sudden and
unexpected.9 The
growing number of patients with heart failure; the aging population in
industrialized countries; and the increasing number of patients in the
Third World with coronary heart disease due to smoking, altered dietary
habits, and a move from rural to urban areas make it likely that the
number of victims from sudden cardiac death will continue to increase
in the coming years. Unfortunately, our efforts in using noninvasive
and invasive tests, such as evaluation of ischemia, hemodynamic status,
neurohumoral responses, and so forth, to identify people at high risk
who die suddenly have resulted in the recognition of only a small
segment of those patients. They are primarily the people with syncopal
or hemodynamically poorly tolerated ventricular tachyarrhythmias,
patients with nonsustained ventricular tachycardia in the presence of
poor left ventricular function in whom a sustained ventricular
tachycardia can be induced, and patients resuscitated from cardiac
arrest. Those patients, once identified, can be helped by implanting an
ICD (Hallstrom et al, unpublished observations, 2000). The number of
defibrillator shocks can often be reduced by prescribing antiarrhythmic
drugs like sotalol and amiodarone.
About 40% of sudden death victims have cardiac arrest as the first manifestation of coronary artery disease. In patients with known coronary heart disease, sudden death is frequently caused by the sudden rupture of an unstable plaque, leading to occlusion of the coronary artery in a vessel previously having only a slight narrowing. Our current tests do not allow us to recognize those patients before plaque rupture. Even if we were able to do so, we do not know what measures to take to prevent plaque rupture. Although molecular genetics has helped unravel the location of genes responsible for the long-QT syndrome (LQTS),11 12 a genetically determined primary electrical disease of the heart contributes to <1% of the sudden death victims. Realistically therefore, only a minority of these individuals can be recognized as being at high risk before the event. Lifestyle changes such as abstinence from smoking, sufficient physical exercise, and control of body weight should be advised as primary prevention measures to reduce heart disease and sudden death. In patients with known cardiac disease, apart from lifestyle changes, other measures to reduce sudden death must be taken, including correcting ischemia, reducing cholesterol, taking ß-adrenoceptor blockers and aspirin, and so forth. Still, we must concentrate on improving the outcome of resuscitation attempts outside the hospital. Early cardiac massage and rapid restoration of normal cardiac rhythm are essential to prevent death and irreversible cerebral damage.13 Better warning systems are needed to recognize cardiac arrest victims to raise an alarm and transmit the exact location of the victim to providers of basic and advanced life support. Also, public-access defibrillation should be encouraged, allowing nonphysicians to use automated external defibrillators (AEDs).14 These advances follow the pioneering work in Seattle of Cobb (Becker et al15 ) and others and must be continued.
Mechanisms of Cardiac Arrhythmias
Basic
The quest to understand basic mechanisms of cardiac
arrhythmias derives in part from the electrophysiologist’s desire to
pair an antiarrhythmic drug that has a specific mechanism of action
with a cardiac arrhythmia initiated or maintained by a specific
electrophysiological
event.16 The hope
was that drugs so tailored could be applied much as we use antibiotics.
Despite >50 years of effort, our failure to attain this goal is due
more to the complexity and heterogeneity of cardiac arrhythmias and the
focused action of antiarrhythmic drugs, mostly "sons of quinidine,"
than the lack of effort by investigators. Well-defined arrhythmias
caused by specific ion channel abnormalities such as the
LQTS11 or
Brugada17 syndrome
may yet yield to such a targeted
approach,12 but the
vast number of clinical ventricular tachyarrhythmias in patients with
coronary heart disease and cardiomyopathies will probably not.
Nevertheless, lessons learned about clinical arrhythmias, albeit not at
an ion channel level, have permitted the application of radiofrequency
catheter ablation techniques based on understanding their site of
origin and/or pathways used, as noted below.
Research at the basic level over the past 50 years has shown that the mechanisms responsible for cardiac arrhythmias can be divided into 2 broad groups: those due to abnormalities of either impulse formation or impulse conduction.16 Inappropriate discharge rate of the sinus node or automatic discharge from subsidiary pacemakers in ectopic sites can cause arrhythmias in the first category. Probably most important, however, is the concept of triggered activity, ie, pacemaker activity consequent to a preceding impulse(s). The preceding impulse triggers an afterdepolarization, which is a membrane oscillation that can reach threshold and initiate 1 or more cardiac responses. When the oscillation occurs before repolarization is completed, it is called an early afterdepolarization (EAD), which appears to be responsible for prolonging the QT interval in the acquired and inherited LQTS and initiating torsades de pointes.18 Increased heart rate and magnesium suppress EADs, which explains the therapeutic efficacy of those treatments in the acquired LQTS. Late or delayed afterdepolarizations may be responsible for some arrhythmias as well and can be initiated by digitalis and other causes of intracellular calcium loading. Perhaps afterdepolarizations initiate some specific types of ventricular tachycardias, such as those arising in the right ventricular outflow area or the left ventricular septum in people with structurally normal hearts, which can be suppressed by adenosine or verapamil, respectively. The most rigorous testing of the concept of pairing a drug with a specific arrhythmia mechanism is in the congenital LQTS, in which the exact ion channel abnormality is known and can be affected by a specific drug. These studies are in their infancy, however.12
It would appear that most clinical arrhythmias are due to reentry, a form of abnormal impulse conduction caused by reexcitation of an area of the heart previously activated. The resulting "cat-chasing-its-tail" tachycardia can occur over anatomically established pathways, such as the atrioventricular (AV) node and an accessory pathway to produce AV reentrant tachycardia, or it can be functional in nature, as in acute ventricular ischemia. Drugs affecting conduction or refractoriness in the reentry pathways can interrupt the reentry tachycardia. When the electrophysiological characteristics of 1 of the pathways are known, for example, the AV node, drugs such as digoxin, calcium channel blockers, and ß-adrenoceptor blockers can be targeted to that tissue, which is often the "weak link" of the tachycardia. Many times, as with reentrant ventricular tachycardias after myocardial infarction, drugs cannot be applied with such precision because the electrophysiology of the pathways is unknown. Furthermore, arrhythmia-initiating mechanisms interacting with the abnormal myocardial substrate can become very complex and lead to unpredictable drug effects, resulting in inadequate arrhythmia control or even a proarrhythmic response. Although understanding the basic electrophysiological mechanisms is unquestionably important, further progress is needed for it to be of help in treating ventricular tachyarrhythmias occurring in damaged ventricles. The paradigm of the LQTS, and perhaps Brugada syndrome, may advance that objective.
Clinical
In the late 1960s, the use of intracardiac catheters
for cardiac activation mapping and programmed electrical stimulation of
the heart opened a new chapter in the diagnosis and management of
clinical
arrhythmias.19
Recording the His bundle
electrogram20 made
it possible to investigate normal and abnormal conduction over the AV
node–His bundle branch system. The reproducible initiation and
termination of supraventricular tachycardias and ventricular
tachycardias by critically timed premature complexes allowed
localization of the site of origin or pathway of an arrhythmia. Those
investigations resulted in our understanding of the mechanisms, such as
reentry and origin of an arrhythmia, which allowed a much better
interpretation of tachycardias and conduction disturbances with the
12-lead ECG.
This knowledge also led to the development of new therapies. Cardiac surgeons began to remove or isolate tissue that was the site of origin of abnormal impulse formation or dissected and interrupted critical parts of the tachycardia pathway. They made incisions in areas where multiple reentrant circuits were responsible for the arrhythmia,21 22 such as in atrial fibrillation.23 Close cooperation between clinical electrophysiologists, anatomists, and surgeons played a crucial role in the development of these curative interventions. The ability to obtain information about tachycardia mechanisms and pathways by programmed stimulation and catheter mapping made it possible to study the effect of pharmacological interventions in patients suffering from tachycardias. In the 1980s, drug selection by programmed electrical stimulation of the heart became increasingly popular. Later, it was realized that in a complex arrhythmia substrate, such as a scar after a myocardial infarction, long-term prediction of drug effect is difficult to obtain. Based on findings from programmed stimulation of the heart, devices were developed to interrupt tachycardias. Starting with "underdrive" pacing followed by "overdrive" pacing, growing sophistication resulted in implantable antitachycardia devices that used pacing algorithms able to cope with rate changes during tachycardia.
Therapy
Transthoracic Electrical Cardioversion and
Defibrillation
Electrical cardiac resuscitation had its beginning
>200 years ago in very crude
attempts.24 In
modern times, Beck et
al25 in 1947 first
applied Wigger’s concepts of defibrillation developed in
animals26 to a
patient and terminated ventricular fibrillation with an AC current
shock to the heart exposed by a thoracotomy. Evolving from AC current
shocks to DC current to creation of more optimal waveforms,
transthoracic electrical cardioversion/defibrillation was quickly
applied to patients with sustained supraventricular and ventricular
tachyarrhythmias.27
Now quite routine, this advance for the first time provided a safe,
effective, and immediate method of terminating tachyarrhythmias that
could be applied to resuscitative needs as well as elective
cardioversion. Indeed, its initial development paralleled the initial
advances in cardiopulmonary resuscitation. And for that purpose, more
recently the AED has been created. This device, operating through
paddles placed on the victim’s chest, interprets the cardiac rhythm
and automatically determines whether a shock should be issued. The AED
is gaining wide-spread popularity for lay public application and has
the potential of reducing the mortality from sudden cardiac
death.15 Efforts to
lower defibrillation thresholds continue, with the advent of biphasic
waveforms. While the electrophysiological basis of shock-induced
defibrillation still is
debated,28 29
there is little doubt that this technique laid the foundation for many
subsequent advances in clinical cardiac electrophysiology. In addition
to serving as the forerunner of the ICD, transthoracic
cardioversion/defibrillation has allowed many interventions, such as
invasive electrophysiological studies, to be applied without fear of
being unable to terminate an induced tachyarrhythmia.
Pacing
Hyman,30
credited with inventing the cardiac pacemaker in 1932, probably
introduced the clinical era of cardiac pacing. Twenty years later,
Zoll31 reported that
the heart could be stimulated transcutaneously by using line-operated
equipment. In 1957, Bakken built a battery-operated external pacemaker
in an electronics repair shop in just a few days at the request of
Lillehei, who was caring for a postoperative child with complete heart
block. The need for a battery-based stimulator became evident when a
power outage rendered line-operated equipment useless. The pacemaker
incorporated an electronic circuit created for the intermittent
pulsation of a metronome, taken from the magazine Popular
Electronics.32
The next step occurred when Furman and
Schwedel33
recognized the drawbacks of transcutaneous pacing and developed the
endocardial pacing approach in 1958. Shortly thereafter, Elmqvist and
Senning34 implanted
the first rechargeable pacemaker to treat a patient with Adam-Stokes
syncope. That first device lasted just several hours, and its
replacement, 8 days. The patient survived and was still alive 40 years
later after numerous pacemaker replacements. Two years after the
pacemaker implant by Elmqvist and Senning, Chardack et
al35 implanted the
first fully transistorized pacemaker. The application of simple
asynchronous pacing, so-called VOO mode, in those early units restored
the patient with complete heart block from a mortality approaching 50%
in 1 year to a normal life span. Although subsequent advances in
cardiac pacing for bradyarrhythmias have unquestionably further reduced
mortality and improved morbidity, none have matched the mortality
reduction gained by the initial VOO pacemaker. Today’s pacemakers are
extremely sophisticated devices, capable of treating tachyarrhythmias
as well as bradyarrhythmias, and incorporate extensive recording
capabilities and a variety of physiological sensors to match the pacing
rate and mode with physiological needs. Many of these pacing features
are standard in ICDs. Recent applications include biventricular pacing
to treat heart failure and biatrial pacing to prevent atrial
fibrillation.
Implantable Cardioverter Defibrillator
Amazing vision mixed in equal parts with tenacity and
zeal enabled Mirowski et
al36 to conceive and
develop the ICD. The details of his saga have been reported many times
and will not be elaborated here. Suffice it to say that 2 treatments,
the invention of the ICD and the application of radiofrequency catheter
ablation, have revolutionized the therapy of patients with cardiac
arrhythmias in ways unparalleled by any other modality. At least 5
studies have now documented the superiority of the ICD over
antiarrhythmic agents in patients with serious ventricular arrhythmias,
both as primary and secondary prevention, permitting the conclusion
that if the patient’s risk of dying is from a ventricular
tachyarrhythmia, the ICD should be the initial treatment of choice
(Hallstrom et al, unpublished observations, 2000). Future advances for
the ICD include smaller devices with increased longevity, improved
leads, waveforms with lower defibrillation thresholds, and the ability
to prevent certain arrhythmias. Improved sensors may
allow monitoring for ischemia or the development of heart failure by
changes in intracardiac pressures or
PO2. Improved
"connectivity" between patient, hospital, and physician may permit
transmission of device parameters and patient information over the
Internet. This "ambulatory CCU" concept could also establish
automatic, closed-loop treatment of a variety of illnesses. For
example, if the device sensed the development of acute ischemia, it
might trigger the infusion of intravenous nitroglycerin from an
implanted drug dispenser or at the minimum, alert the patient of a
change in clinical status and to seek physician assistance. If the
device sensed the development of heart failure, it might automatically
alter its pacing rate, AV interval, or V-V interval (for
dual-ventricular pacing devices) or warn the patient to seek medical
help. As with the impact of VOO pacing on mortality, however, the ICD
in its present configuration has probably realized its major effect.
Nevertheless, further advances will continue to incrementally reduce
mortality while improving morbidity. Several studies are testing
whether the ICD will increase survival in heart failure patients who
have not yet had an arrhythmic event. If this proves to be the case and
if large numbers of patients will require ICD implantation, then we
must call for the manufacture of a "shock box," an
inexpensive ICD with limited function and the ability
to deliver perhaps 6 or 8 shocks, which would be implanted
prophylactically in these patients.
Antiarrhythmic Drugs
Antiarrhythmic drugs have had a checkered history.
Beginning 50 years ago, drugs such as quinidine were used routinely in
patients, without monitoring, to treat virtually all symptom-producing
arrhythmias, with the assumption that because the drugs had
demonstrable electrophysiological actions and were called
antiarrhythmic, they naturally functioned in that fashion. Despite an
early study reporting "quinidine syncope" due to torsades de
pointes,37
quinidine, procainamide, and disopyramide were used to suppress simple
premature ventricular complexes or tachycardias, sometimes in ascending
doses to cardiovert atrial fibrillation (quinidine), and were commonly
given prophylactically to patients after myocardial infarction. With
the development of the CCU, lidocaine was added to that list and was
administered prophylactically to patients with acute myocardial
infarction to suppress premature ventricular complexes that exceeded 4
or 5 per minute, were multiform, or occurred in the T-wave vulnerable
period. Drugs such as bretylium, still part of some resuscitative
strategies, achieved approval with very meager scientific data. No
controlled trials supported the application of these
agents.
The Cardiac Arrhythmia Suppression Trial (CAST)38 dramatically changed how we used antiarrhythmic drugs for ventricular arrhythmias by demonstrating that class IC agents increased mortality while suppressing ambient ventricular ectopy and ushered in a new era of outcome-based antiarrhythmic drug decisions. CAST also taught us that a proarrhythmic response could occur months after drug initiation, that a change in the myocardial substrate (presumably, the development of ischemia) could alter drug-substrate interaction to create a lethal arrhythmia, and that some surrogates for death, such as premature ventricular complex suppression, were invalid. To date, of the class I and III antiarrhythmic drugs, only amiodarone has been shown to reduce arrhythmic deaths in patients after myocardial infarction39 and to be the most effective antiarrhythmic drug in maintaining sinus rhythm in patients with atrial fibrillation.40 More recently, angiotensin-converting enzyme (ACE) inhibitors41 and spironolactone42 have also been shown to lower cardiac death in patients with heart failure. While explanations ultimately involving reduced sympathetic effects are hypothesized to explain the action of these drugs, the mechanism(s) by which they alter the arrhythmogenic substrate is not known. However, given the success of amiodarone, a "dirty" drug that affects all of the Vaughn Williams drug categories, ß-adrenoceptor blockers, and now ACE inhibitors and aldosterone blockers, coupled with the inefficacy or actual harm produced by most other antiarrhythmic agents,43 it may be time to rethink the concept that blocking a single, specific ion channel in the heart, Ikr for example, with a distinctive molecule that has no other actions can ever be antiarrhythmic for large groups of patients who have complex ventricular arrhythmias.
Acute termination of sustained supraventricular tachycardias was achieved 50 years ago with intravenous phenylephrine, titrated to elicit a reflex vagal response by acutely elevating the systolic blood pressure to approach or exceed 200 mm Hg, or administration of digitalis preparations. ß-Adrenoreceptor blockers, calcium channel blockers, and then adenosine eliminated the need for such an approach by modulating AV nodal conduction and refractoriness for safe and effective treatment of supraventricular tachycardias.
Catheter Ablation
In the early 1980s, Scheinman (Gonzalez et
al44 ) and
Gallagher et al45
demonstrated that a high-energy shock delivered over a catheter placed
against the bundle of His could interrupt AV conduction to create
chronic, complete AV block. Although this treatment had a relatively
restricted application for patients with atrial arrhythmias, such as
atrial fibrillation with an uncontrolled rapid ventricular rate, it
introduced the concept of being able to alter the electrophysiology of
the heart with a catheter. What followed was an amazing new therapeutic
development that offered cures for patients with a variety of
supraventricular and ventricular tachycardias. Radiofrequency energy
rapidly replaced the high-energy shocks as the technique was applied to
patients with AV nodal
reentry46 and
accessory pathway47
tachycardias. Catheter ablation therapy continues to evolve, with
investigation of new electrodes, catheters, and energy sources.
Presently, radiofrequency catheter ablation can eliminate virtually all
tachyarrhythmias with success rates between 70% and 100% and
complication rates of <1% to 2%, depending on the nature of the
tachycardia and the skill of the
electrophysiologist.48
Tachyarrhythmias that still offer a challenge include atrial
fibrillation, although new observations showing a focal origin have
facilitated
ablation,49 and
ventricular tachyarrhythmias in patients with structural heart
disease.
Genetics
Several types of inherited defects in genes encoding cardiac ion channel proteins have been identified to cause cardiac arrhythmias. These abnormalities have been explored in greatest depth in the LQTS. Presently, there are at least 6 variants of the LQTS first described by Jervell and Lange-Nielsen (with sensorineural deafness) in 1957 and then by Romano et al and Ward (with normal hearing) several years later. The Romano-Ward syndrome is autosomal dominant, whereas homozygous mutations of LQT1 appear to be responsible for the Jervell-Lange-Nielsen syndrome.11 The ionic abnormalities found so far involve a reduction in the repolarizing currents provided by K+ channels or an increase in the inward plateau Na+ current. These ionic alterations serve to increase intracellular positivity, which results in a prolongation of atrial and ventricular repolarization and creation of the milieu for development of EAD-induced ventricular18 and possibly atrial50 51 tachyarrhythmias. Families with no linkage to any known locus have been described, and therefore, it is likely that additional genetic abnormalities will be described in the future. Interesting phenotypes have been noted, with patients who have LQT1 at risk for sudden death during emotional or physical stress, particularly during swimming. Individuals with LQT2 are at risk both at rest and during exercise and especially during acoustical stimulation.11 12 LQT3 patients appear to be at greater risk during sleep. Interestingly, the abnormal gene responsible for LQT3 has also been found to cause the Brugada syndrome.52 Although genotype-directed therapy is being tested, the fact that patients with identical mutations can have different phenotypes and some may manifest no phenotype at all challenges this approach. These latter patients may be at risk for developing drug-induced ventricular arrhythmias.53 Thus, identical genetic abnormalities can have different clinical expressions, and therefore, the type of gene mutation may not necessarily predict the clinical phenotype. Nevertheless, the LQTS is once again serving as a "Rosetta stone,"54 this time by providing new insights into the paradigm of genetically based molecular causes of cardiac arrhythmia.
Conclusions
These 10 major advances over the past 50 years have radically changed the treatment of patients with arrhythmias. Although the next 50 years will undoubtedly explore genetics-based diagnosis and treatment, most of these top 10 advances will remain as fundamental clinical concepts, part of the everyday practice of cardiology. No better testimony of their importance to patient well-being could exist.
Acknowledgments
This work was supported in part by the Herman C. Krannert Fund; by grant HL-52323 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Md; and by the Wijnand N. Pon Foundation.
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