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Birth follows pain. Resurrection follows death.
Progress follows failure. The largely unexpected results of CAST1
were the stimulus for a complete reassessment of the therapeutic strategies to be employed
for the prevention of sudden cardiac death in patients affected by ischemic heart disease.
The results were indeed so totally unexpected that the authors of the study had planned
their statistical analysis on only a one-tail p value because they had not even taken in
consideration the alternate possibility, namely that the drugs under study could have
produced damage instead of benefit. Since then, the cardiological world has become
painfully aware of the impossibility of ruling out a priori the chance for an
antiarrhythmic drug to produce the effect opposite to that initially sought, and SWORD2 has further reminded us of this reality.
The results of CAST were so disconcerting that the entire arrhythmia world, from
practicing cardiologists to academic investigators, from drug companies to regulatory
agencies, went into disarray. It was at that time that the Working Group on Arrhythmias of
the European Society of Cardiology appointed two Task Forces first to understand the
implications of CAST3 and then to attempt the
development of a new, and hopefully more rational, approach to the treatment of cardiac
arrhythmias4.
The members of the Sicilian Gambit proposed in their first document4
the concept of the "vulnerable parameter" as a rational approach to the
identification of a specific target for the most effective therapy. There were two
underlying assumptions. The first was that for each arrhythmogenic mechanism an alteration
in one or more of several electrophysiological properties will be sufficient to terminate
the arrhythmia or to prevent its initiation. The second assumption was that among the
several possible effective changes in electrophysiological properties, usually one is most
susceptible to alterations while manifesting a minimum of undesirable effects on the
heart. This property is called "vulnerable parameter". These concepts were
further refined in the subsequent documents produced by the members of the "Sicilian
Gambit"5,6 and have progressively evolved toward
the identification of molecular targets for the prevention or termination of specific
arrhythmias.
An example of this strategy could be the identification of ventricular refractoriness
as a "vulnerable parameter" for some reentrant arrhythmias. For those in which a
short excitable gap is thought to exist, a logical approach is to prolong ventricular
refractoriness with the objective of having the reentrant wave of excitation to encroach
on its own refractory tail, thus interrupting the reentrant circuit. Prolongation in
ventricular refractoriness is the consequence of a prolongation in action potential
duration and this is achieved by blocking some of the outward repolarizing K+
currents. Among the various K+ currents, the delayed rectifier IK
appears as a most logical target and, as a consequence, many of the recently developed
antiarrhythmic drugs were designed to block either one or both of its two main components,
IKr and IKs. In the parlance of the "Sicilian Gambit",
ventricular refractoriness and more specifically the ventricular action potential duration
(to be prolonged) is the "vulnerable parameter" and the target is represented by
IK.
A sudden shift has taken place during the last few years when the progress in
molecular biology has raised, for a few diseases, the possibility of a truly molecular
approach to a truly molecular target. The best example, and also a useful paradigm, is
offered by the congenital long QT syndrome (LQTS).
There is indeed reason to single out LQTS from other arrhythmogenic disorders because
recent data provide insight onto its pathophysiology with clues for the use of molecular
targets for antiarrhythmic therapy that should have increased application in the future.
There are at least 6 chromosomal loci to which LQTS may be linked, and at 4 of them the
mutated genes have been identified7-10. All of them
encode for ion channels involved in the control of action potential duration. One, SCN5A,
located on chromosome 3, is the gene for the Na+ cardiac channel and the LQTS
mutations produced an excess of late inward Na+ current. Another, HERG, located
on chromosome 7, is the a K+ channel gene encoding for IKr, the
rapid component of the delayed rectifier IK and the LQTS mutations produce a
decrease in outward K+ repolarizing currents. Finally, KvLQT1 and KCNE1,
located on chromosomes 11 and 21, encode for two essential components of IKs,
the slow component of IK, and the LQTS mutations result in a loss of K+
repolarizing current. The bottom line is that LQTS exemplifies how heterogeneity of
alterations and mechanisms can all ultimately lead to nearly identical
electrocardiographic and clinical manifestations. These data also suggest that
gene-specific therapy, directed either to the correction of the electrophysiologic
consequence produced by the various mutations or to induce overexpression of the wild
(normal) LQTS genes, may provide a previously unforeseen approach to a definitive
treatment of this disease.
A molecular approach may becoming reality in a not so distant future also for other
more common cardiovascular diseases with a significant arrhythmic component. A prime
example is represented by congestive heart failure. Among patients with heart failure who
die, 35-50% of the deaths are sudden and unexpected11,12.
Electrocardiographic analysis frequently shows significant abnormalities of ventricular
repolarization, and it is reasonable to suspect that, as in many other conditions13, QT prolongation may increase the risk for sudden
cardiac death. As a matter of fact, a recent study has demonstrated a significant
association between increased Q-T dispersion and sudden death14.
The underlying mechanism for prolongation of action potential duration has become apparent
by a series of studies based on ventricular cells obtained from hearts of patients
undergoing transplantation15. The main finding is that
these cells show a significant reduction in the current density of two important K+
repolarizing currents, namely the inward rectifier, IK1, and the transient
outward current, Ito. It is therefore highly tempting to speculate that a novel
approach might be represented by inducing overexpression of IK1 and of Ito.
The goal of this molecular therapy would be at correcting the molecular abnormality
responsible for the increased propensity for life-threatening arrhythmias and for the
premature deaths of many patients.
How did we get here? It may be worth reviewing briefly some of the steps that have
taken place and of some of the newly emerged concepts. Despite the fact that the first
clones of ion channels have been identified in the mid-eighties, only during the last few
years did several investigators turn their interest toward the establishment of critical
links between ion-channel proteins and human diseases. Neuroscientists were forerunners in
the field when they identified mutations in voltage gated ion channels in diseases such as
hyperkalemic periodic paralysis16, paramyotonia
congenita17 and episodic ataxia18.
Cardiologists followed shortly afterwards with the Long QT syndrome, the first example of
a cardiac ion channel disease; right now, the identification of another arrhythmogenic ion
channel disease is close to be published.
The impact of research on arrhythmogenic congenital diseases would have been far less
striking without the impressive development of knowledge about the factors that regulate
the expression of ion channels in the human heart. The simultaneous involvement of both
basic scientists and clinicians has contributed to the rapid development of the new field
of "molecular arrhythmology". The rather revolutionary view that is being
progressively accepted is that ion channels in the heart should not be regarded as a
static features of the cardiac muscle but that, on the contrary, they represent a
renewable source of proteins with a dynamic adaptation to changes in the surrounding
environment. Ion channels are unequally distributed across the myocardial wall19 and in different regions of the heart20 and, in conditions such as ventricular dilatation and
failure11 or hypertrophy21
they may increase or decrease their number resulting in the unique electrophysiologic
profile of the diseased heart. The fact that the ion channels distribution is different in
a healthy, failing, and hypertrophied hearts helps to understand why the use of the same
molecules to treat electrical disturbances in these different conditions has been so
disappointing, as manifested by the outcome of most clinical trials of the last decade.
To further complicate this picture, it is now evident that ion channels differ during
fetal and adult life22 and that regression toward the
fetal pattern may occur in disease states as it has been demonstrated for structural
proteins in the heart23. Elucidation of the mechanisms
leading to electrical remodeling of the heart is one of the next challenges, because most
of the regulating factors that influence the expression of ion channels are still
undefined. Studies performed in clinical models of cardiac denervation, such as the Chagas
disease24, imply the autonomic nervous system in the
modulation of ion channels expression.
With this perspective, it is not surprising that antiarrhythmic therapy with drugs
designed to modify cardiac activation and repolarization in the "normal" heart
may fail to protect the "abnormal" heart in which both the distribution and
density of ion channels is altered. Looking at the future of antiarrhythmic therapy it
becomes reasonable to expect and hope that molecular modulation of ion channels, achieved
by either the restoration of their physiologic function and distribution or by the more
futuristic correction of mutated genes, may provide a new therapeutic strategy for the
management of cardiac arrhythmias.
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