(Circulation. 1999;99:674-681.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III1 2
From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands.
Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology and Electrophysiology Laboratory, Fondazione "S. Maugeri" IRCCS, Via Ferrata, 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it
Key Words: death, sudden • genetics • arrhythmia • molecular biology • electrophysiology
 |
Part III: Molecular Basis of Cardiac Electrophysiology and Arrhythmias |
|---|
 Top Part III: Molecular Basis... Appendix 1References |
|---|
In Parts I and II of this article,* we discussed monogenic arrhythmic disorders. These are determined or favored by an inborn alteration and for the most part are characterized by a single genetic alteration. This has allowed the use of "paradigms"; namely, diseases, such as the long-QT syndrome (LQTS), in which it has been possible to trace specific mutations on ion channel genes to their electrophysiological consequences in the patient. Unfortunately for the practicing cardiologist, these "simple" diseases constitute only a small part of the clinical conditions associated with cardiac arrhythmias. The majority of cases affect patients in whom the arrhythmogenic substrate is complex. Indeed, the expression of the molecular systems responsible for normal and abnormal electrical activity vary significantly, depending on a variety of factors, including age, regional factors (type of cells, myocardial perfusion), and such underlying chronic diseases as cardiac hypertrophy, myocardial infarction, and heart failure.
The study of this complex system of interacting molecular functions requires an approach somewhat different from that required to consider monogenic disease. Accordingly, in this section we discuss broader themes that are essential to understand the integration of gene expression, ion channel function, and cell coupling in multicellular networks as a first step toward the comprehension of more frequent and more complex arrhythmogenic conditions.
Diversity of Gene Expression in the Heart
Understanding cell-to-cell variability in the cardiac action
potential shape and the mechanisms underlying impulse propagation is
the key to understanding normal and abnormal cardiac electrophysiology.
Much of this variability can be attributed to variability in the
characteristics of individual ion currents whose integrated behavior
determines the shape and duration of action potentials in individual
cardiac cells, as well as to variability in cell-to-cell
communications. Ion currents are now recognized to flow through
specific pore-forming membrane proteins called ion channels. The first
gene encoding an ion channel protein was cloned in 1984,95
and the succeeding decade and a half has seen the cloning of genes
encoding most ion channels expressed in heart and in many other
tissues.96 97 98 Many of the proteins these genes encode
share common structures and can be viewed as members of the same
superfamily. For example, Figure 3
* shows
the tremendous diversity of mammalian genes that make up the family of
potassium channel genes. Because potassium channels are made up of 4
ion channel 
-subunit proteins, which are not necessarily identical,
the potential for diversity in potassium currents is even greater than
shown. This is further compounded by the identification of ancillary
subunits (the products of different genes) that can assemble with
potassium channel tetramers to modulate their
function.99 100 101 Figure 4
illustrates the major ion currents in heart and the genes whose protein
products are thought to form their structural basis. The dramatic
increase in molecular genetic information underlying cardiac function
is not confined to ion channels but rather has extended to multiple
other genes, including those controlling cell-to-cell communication
(the connexins, Cx), the contractile apparatus, and cardiac
development, to name a few. With this cloning effort have come
important advances not only in understanding mechanisms of normal
cardiac function but also in new insights into the mechanisms
underlying common cardiac diseases and their therapy.
|
|
A common method of studying individual cardiac ion channel gene function is to express the gene of interest in noncardiac (heterologous) study systems, such as mammalian cell lines or the eggs of the African clawed toad, Xenopus laevis. In some cases, expression of a single gene in such heterologous systems is sufficient to reproduce the physiological and pharmacological characteristics of a specific cardiac ion current; HERG expression to recapitulate IKr is an example,102 although coexpression of the minK subunit may increase IKr amplitude.103 104 The systems have been especially valuable in delineating the functional consequences of ion channel gene mutations, although it should be recognized that mechanisms other than a simple dominant negative effect on channel gating (eg, altered trafficking) may also play a role.
In other cases, faithful recapitulation of a specific cardiac ion
current requires coexpression of >1 gene. Heterotetramers of
Kv4.2 and Kv4.3 may determine the
Ito in some species.105
Other examples include coexpression of a structural gene and an
ancillary subunit; one good example is the finding that coexpression of
KvLQT1, a member of the potassium channel family shown in
Figure 3
, with the minK gene is required to
recapitulate
IKs.13,14
Another example is the -ß1 interaction
during the development of an adult sodium current as described below.
In yet other cases, a gene product (eg, Kv2.1) can be detected in
heart without a recognized counterpart among the known ion currents,
and ion currents (If) remain for which no
corresponding gene has yet been identified. One very important
observation is that ion channel genes are virtually never expressed
exclusively in the heart. Thus, mutations or blocking drugs may affect
not only cardiac function but also function in other organs. The
best-described example to date is the deafness displayed by patients
with the recessive (Jervell and Lange-Nielsen) form of
LQTS.4 This arises because the 2 genes involved in
the disease, KvLQT119,20 and
minK,16,106 are expressed not only in
the heart but also in the inner ear, where together they control
endolymph homeostasis.107 It is not yet known whether
parent carriers, who have mild, usually but not always
asymptomatic mutations in
KvLQT120 or
minK,15 display subtle defects in
hearing. This is but one example of the potential for a molecular
genetic explanation for a diversity of symptoms through common
mutations affecting function in multiple organs.
Development
One well-recognized form of variability in cardiac function is the
stereotypical changes that are observed during development. Much of the
information has been gathered in small rodents and may not be directly
applicable to humans, but it may be important because a common form of
cardiac response to injury is regression to a fetal phenotype.
Whether, for example, the
electrophysiological changes associated
with hypertrophy (eg, in patients with hypertension or
heart failure) represent such a patterned response is an
important consideration. Understanding the mechanisms underlying such a
change in phenotype may be an important step in the prevention
of arrhythmias in these common acquired disorders of cardiac
function.
The earliest stage at which ion currents have been recorded from
heart tissue is embryonic (postcoital, pc) day 11 in mouse
(normal gestation period, 20.5 days). At this stage, the predominant
inward current is L-type calcium current
[ICa(L)], and the predominant outward
current is the rapidly activating component of the delayed rectifier,
IKr.108 109 Sodium
current (INa) appears later and increases
markedly just before birth.109 There are important
differences between sodium current recorded in neonatal animals and
those recorded in adult animals110 111 :
INa in neonates is smaller; it
activates, inactivates, and recovers from
inactivation more slowly than that in adults; and it has a more
positive voltage dependence of inactivation than that in adults. Some
data suggest that this difference between neonatal and adult sodium
current may reflect expression of a ß1-subunit
and/or -ß1-assembly to produce the
"mature" phenotype112 113 and that this
change may reflect the sympathetic innervation of the heart that occurs
around the time of birth. This may be but one example of a more general
influence of sympathetic innervation as a modulator of cardiac
electrophysiology.114 It is likely that multiple
mechanisms will be identified. The possibility that regional cardiac
denervation may play a role in acquired diseases (eg, myocardial
infarction) is an obvious one that requires further
study.115 Another intriguing observation during
development is the consistent embryotoxicity of specific
IKr blockers, such as dofetilide or
almokalant, in the rat.116 Because
IKr is the predominant (if not the sole)
repolarizing current at this stage,108 it has been
postulated that embryotoxicity is due to failure of cardiac
repolarization, with death due to arrhythmias secondary to
triggered activity (which have been demonstrated under these
experimental conditions) or simply membrane depolarization. Whether
similar considerations apply to humans has not been determined.
The pattern of expression of the connexins, which form the gap junction channels and belong to one gene family, also varies during development. Cx43 mRNA is detectable in mouse heart from day 9.5 pc. Initially, it is expressed only in ventricle, but later it spreads throughout the whole heart. Two weeks after birth, the message starts to diminish again to a steady level that is maintained during adulthood.117 Cx40 is detected from 9.5 days pc. The message is initially confined to atrium and left ventricle, but during development it spreads throughout the whole heart.118 After 14 days pc, Cx40 message starts to diminish in the ventricles from epicardial to endocardial until in the adult, Cx40 is restricted to both atria and the proximal conduction system.117 Cx45 mRNA is expressed from day 11 pc at a constant level throughout the whole heart until week 3 postpartum, when it starts to decrease until in adulthood, only low-level expression in the proximal conduction system is detected.117
Regional Diversity in Cardiac Electrophysiology
Although heterogeneity of cardiac
electrophysiology is increasingly recognized as a contributor to
cardiac arrhythmias, it should also be recognized that there is
substantial heterogeneity in the
electrophysiological properties of
individual cells even under physiological
conditions. A trivial example is the differences among the
electrophysiological properties of
sinoatrial node, atrium, AV node, conducting system, and
ventricular myocardium. These differences
presumably reflect variability in expression and/or function of the
repertoire of ion channels, whose integrated activity determines the
distinctive action potentials in each of these regions. More recently,
it is increasingly recognized that there is considerable potential for
cell-to-cell variability in action potentials and gene expression
within such specified regions. For example, a survey of atrial myocytes
revealed a consistent Ito only in
60% of cells, a consistent IK
in 15% of cells, and both currents in 30% of
cells.119 Studies of mRNA expression have also
demonstrated striking cell-to-cell variability in expression of
individual ion channel genes.120 Two LQTS genes,
HERG and KvLQT1, were identified in a majority of
cells in most regions. In contrast, minK was most abundant in
sinoatrial node (in 33% of cells) but was much less abundant in
ventricular muscle cells (10% to 29%). This is
consistent with a more recent report that, at least in the
mouse, minK expression appears to be restricted largely to
the conducting system.121 Similarly, M cells, which
as described below appear to play a role in the genesis of
arrhythmias related to a long QT interval, have
distinctively long action potentials that prolong markedly at slow
heart rates,122 a characteristic also seen in Purkinje
cells.122 124 One report suggests that this distinctive
action potential behavior is paralleled by a reduction in
IKs (compared with endocardial and
epicardial cells).125
Electrophysiological studies have identified Kv4.2 and/or 4.3 (depending on the species) as the ion channel gene whose expression in heterologous systems results in a current most closely resembling human Ito.126 One of the important features of human Ito is its usually rapid recovery from inactivation.127 It was this observation that first raised the suggestion that Kv1.4, an initial leading candidate for Ito, might not, in fact, encode this current, because Kv1.4 recovers very slowly from inactivation.128 Interestingly, the human endocardium also displays an Ito, but one that, unlike that recorded in epicardium, recovers from inactivation very slowly and is therefore not regularly observed in endocardial action potentials.127 It therefore remains conceivable that although Kv4.x encodes epicardial Ito, expression of other channels, including Kv1.4, may still contribute to the electrophysiological properties of cells in other regions.
The connexins are also expressed in a chamber-specific and
tissue-specific fashion. In heart, Cx40, Cx43, and Cx45 have been
detected at the protein level.129 The phosphoprotein Cx43
is the most abundant cardiac connexin. It forms gap junctional channels
with a main conductance of 45 pS between cardiac myocytes in all
parts of the heart, with the possible exception of sinoatrial and AV
nodes. In ventricle, Cx43 is more abundant in the intercalated disk
than in the lateral cell borders, which partially explains anisotropic
impulse conduction. In atrium (with the exception of the crista
terminalis), the difference between end-to-end and side-to-side
connections is much less pronounced. Although Cx43 has been reported to
be present in sinoatrial node,130 131 in atrial cells
it is probably intercalated between the pacemaker
cells.132 Rabbit sinoatrial node pacemaker cells proper
are coupled by high-conduction (250-pS) channels formed by an
unidentified connexin (Verheule S, Jongsma HJ, 1998, personal
communication). In atrial gap junctions, Cx40 is colocalized with
Cx43.129 Cx40 is also a phosphoprotein, with a main
conductance of 160 pS. Guerrero et al133 presented
evidence that Cx40 and Cx43 contribute equally to impulse conduction in
atrium. In most species (including humans), Cx40 is also found in the
proximal conduction system. Cx45 forms channels with a conductance of
20 pS that are very sensitive to transjunctional voltage; ie, even
at small voltage differences between neighboring cells, Cx45 channels
close quickly. Cx45 has been reported by some authors134
to be abundantly present in all parts of the heart, but others find
it only in part of the conduction system and in very limited amounts in
the rest of the heart. The role for Cx45 in impulse conduction has not
yet been established.
Integration of Ion Channel Function Into the Cellular
Environment
Although ionic channels and connexins participate in the
generation of the cardiac action potential and in cell-to-cell
communication, it is important to recognize that experimentally,
single-channel data are obtained primarily in preparations that are
removed from the cardiac cell environment (eg, membrane patches, cloned
channels in Xenopus oocytes). Figure 5 is a schematic of a cardiac
ventricular myocyte, demonstrating the complex
physiological environment in which ion channels
function to generate an action potential.135 The
cellular environment is highly interactive and modulates the behavior
of the single channel through interactions with other channels or with
the ionic milieu of the cell. An example is illustrated in the diagram
in Figure 6. In this scheme, the
ICa(L) induces Ca2+
release from the sarcoplasmic reticulum through the
Ca2+-induced Ca2+ release
process.136 The released Ca2+
in the myoplasm, in turn, modulates several ionic currents [including
ICa(L) itself].135 In
Figure 6, the myoplasmic Ca2+ is shown to
increase the conductance of IKs, to drive
INaCa for the purpose of
Ca2+ extrusion, and to participate in the
inactivation of
ICa(L).137 138 139 The
effect on the action potential is complicated; increased
IKs acts to shorten the action potential
duration (APD), as does reduced ICa(L).
INaCa is an inward current (when operating
to extrude Ca2+ from the cell), and its
augmentation acts to prolong APD. The net effect depends on the
quantitative balance of these processes. This balance can depend on the
basal expression of these channels or of the proteins (such as kinases)
that regulate their activity, diseases or other processes that modulate
the expression, and other important factors, such as rate or adrenergic
activity. Importantly, many of these latter processes may also be
modulated by changes in intracellular calcium.
|
|
The example above serves to illustrate a most important point, namely, that the current through an ion channel is determined by its intrinsic kinetic properties and its interaction with the cellular environment. Because of the highly interactive nature of the cell, altered function of a particular channel (eg, due to modulation by calcium) will have an indirect influence on the currents through other channels. For example, the late current that underlies the LQT3 form of LQTS acts to depolarize the membrane during the plateau phase of the action potential. The increase in membrane potential, in turn, alters the magnitudes and time courses of other plateau currents [eg, ICa(L), IKr, IKs], which together determine the APD.
The concept that the action potential is determined by the interaction of various ionic currents is increasingly well appreciated in the context of LQTS. The action potential plateau is maintained by a delicate balance between inward (depolarizing) and outward (repolarizing) currents. In LQTS, the action potential is prolonged by an increase of an inward current (late INa in LQT3) or a decrease of an outward current (IKs in LQT1, IKr in LQT2). It should be emphasized that the effect on the action potential could be very different for the different mutations. For example, the generation of an early afterdepolarization at plateau potentials (phase 2 early afterdepolarization) involves recovery and reactivation of ICa(L).137 138 This can be achieved if the action potential plateau is sufficiently prolonged at a specific range of membrane potential.139 140 141 It is conceivable that such conditions are created by some mutations but not by others.
Similarly, distinctions can occur in the rate-dependence of APD. Through the process of adaptation, action potentials shorten with increasing heart rate.142 This phenomenon raises the possibility of a depression of early afterdepolarizations with fast pacing in LQTS. Recently, it was found that LQT3 shows much greater shortening of QT interval with an increase in heart rate during exercise than the other LQTS types.29 Assuming that the QT interval reflects the degree of APD prolongation in LQTS, it is possible that fast pacing has a greater effect in LQT3 because of the specific involvement of INa in this syndrome. A possible explanation is that with fast pacing, Na+ accumulates in the cell, lowering the Na+ gradient across the membrane and the associated electrochemical driving force for Na+. Through this mechanism (or altered function of the electrogenic sodium-calcium exchanger), the magnitude of INa is reduced. The effect of such reduction will be negligible during the rising phase of the action potential, when INa is so much larger than other currents. However, the plateau INa contribution through mutant channels is of a much smaller magnitude and could be significantly affected by such changes. As stated earlier, this current operates at a critical time, when the action potential is determined by a very delicate balance of small currents. It is conceivable, therefore, that such a small reduction of late INa during this phase could result in shortening of APD at fast rates.
Ion Channel Function in Multicellular Networks
The first section of this part described the diversity and
variability of ion channels involved in cardiac electrical excitation,
and the second illustrated the level of complexity related to the
integration of individual channels into whole-cell function. Assembling
single cells in the multicellular excitable tissue introduces further
significant interactions between ion channel function and structural
properties of the tissue. These interactions play an important role in
depolarization, repolarization, and arrhythmogenesis.
Interaction Between Cell-to-Cell Coupling and Ion Channel
Function.
The simplest model used to explain cardiac electrical propagation
was originally derived from conduction models developed for the nervous
system. In this model, cardiac cells are merged into a syncytium-like
conducting structure composed of a cell membrane carrying the ion
channels that generate the action potential and a single continuous
intracellular space (in this space, the electrical conductances of the
cytoplasm and the gap junctional connexons are merged together). Many
important insights into the electrical propagation process have been
derived from this so-called "continuous" model.143 It
has been successfully applied to describe global effects of
inhibitors of Na+
channels,144 of acute myocardial
ischemia,145 and of
hypoxia/anoxia146 on conduction. However, in many
instances, more complicated models are needed to describe the
conduction process appropriately.
A first step in describing the relation between electrical propagation
and cardiac structure more closely involved simulation of single-cell
chains with interconnections representing the gap
junctions.147 Although the properties of such models are
not markedly different from the "continuous" model when electrical
cell-to-cell coupling is normal, a distinctly different behavior is
unmasked once the electrical coupling of the cells diminishes.
Interestingly, this behavior includes feedback interaction between
cell-to-cell coupling and ion channel function. Partial closure of
connexins (ischemia, hypoxia145 146 ) or a
decrease in expression (heart failure148 ) of connexins
might affect conduction in several ways. First, conduction velocity
decreases to a much greater extent than with inhibition of ion
channels149 and can reach a few centimeters per second or
be even slower. Accordingly, reentrant arrhythmias that occur
in partially uncoupled tissue can form circulating excitation of very
small dimensions (microreentry). By contrast, simulations suggest that
depressed INa alone cannot account for this
phenomenon. Second, a change in cell-to-cell coupling feeds back on the
way ionic channels in the membrane are activated and on the
role of ionic channels in conduction (and most probably,
repolarization). This is illustrated in Figure 7, which depicts a row of simulated cells
in a state of advanced cell-to-cell uncoupling. Because of the high
degree of discontinuity that is introduced by the uncoupled cells,
there is a long conduction delay between the cells. Because the action
potential in the driver cell has to furnish local electrical circuit
current to the driven cell, this current has to flow as long as the
driven cell has not reached its threshold for depolarization, ie, for
activation of the Na+ inward current. In the
normal case of propagation, the conduction delay between 2 cells is
very short. During this time, the Na+ channels of
the driver cell are open and furnish sufficient electrical charge to
excite the driven cell. With advanced cell-to-cell uncoupling and the
concomitant delay, the inward Na+ current will be
inactivated before the driven (downstream) cell reaches
threshold, and consequently, flow of Ca2+ inward
current later during the action potential is necessary to ensure
propagation. Thus, the conduction process can change from being solely
Na+ current–dependent to being
Na+ and Ca2+ inward
current–dependent, merely by a change in the degree of cell-to-cell
coupling.149 150 Feedback interactions between
electrical coupling and ionic current flow are also expected to occur
during the action potential plateau and during repolarization. Because
of the small ion current density and the high membrane resistance
during the action potential plateau,151 the electrical
interactions between adjacent tissue regions are stronger and extend
over longer distances during this phase than during rest or during the
action potential upstroke. As a consequence, differences in intrinsic
APDs among adjacent tissue regions will be relatively small during
normal cell-to-cell coupling and will be unmasked during uncoupling. In
this way, the reduction of electrotonic interaction by cell-to-cell
uncoupling is predicted to unmask intrinsic heterogeneities in
repolarization, with both events serving to promote reentrant
arrhythmias.
|
Interaction Between Tissue Structure and Ion Channel
Function
As with the discrete pattern of gap junctions at the microscopic
level, the macroscopic cardiac structure introduces obstacles and
discontinuities for propagating electrical waves. Typical examples of
discontinuities are branching fibers (Purkinje system, atrial
trabeculae) and/or connective tissue layers (remodeled
ventricular tissue in infarcted and/or hypertrophic hearts,
normal midmural layers of normal hearts,152
ventricular trabeculae in aging
myocardium153 ). Such discontinuities have been
shown to affect membrane channel function. In any situation in which
electrical waves propagate through anatomically discontinuous tissue
and emerge from an isthmus,154 turn around the end of an
obstacle,155 or emerge from a small fiber into a large
tissue mass,156 157 the propagating wave becomes curved.
In a curved wave front, the mismatch between the excitatory local
current produced by the excited cells upstream and the electrical load
of the nonexcited cells ahead of the wave front downstream affects both
conduction velocity and the activation of ionic currents. At a convex
wave front, this mismatch will lead to a local conduction delay and to
a localized increase of the amount of depolarizing inward
current.156 Conversely, at a concave wave front (or,
similarly, at a site of collision), conduction velocity will locally
increase and the inward current will be locally
reduced.158 This dependence of ionic current activation on
wave-front curvature is likely to be responsible for the larger effect
of inhibitors that bind to open Na+
channels at sites at which the propagation wave is convex than at sites
at which it is linear.159 The curvature of the wave front
will also play an important role in determining the ionic channels
involved in impulse propagation. Thus, at divergence points, if the
wave front is markedly curved, large local conduction delays result. As
with the case of advanced cell-to-cell uncoupling (see Figure 7), the Ca2+ inward current then becomes
essential for propagation, and application of
Ca2+ entry blockers produces localized conduction
block.160 Interestingly, the interaction between the
macroscopic tissue architecture and excitation, leading to local
divergence or convergence of wave fronts and changes in ion channel
function, is further modulated by the degree of local gap junctional
coupling.161
Prospective
In the near future, most genes responsible for inherited
arrhythmogenic conditions will be identified and the genomic structure
of disease-related genes will also be defined. This will produce
results that are needed for successful management of patients and
families. One major result will be the definition of the "molecular
epidemiology" of inherited arrhythmogenic
conditions. Qualitative statements such as "rare" or "common"
should be replaced by actual numbers defining the prevalence of each
condition in the general population and the relative prevalence of each
variant of a disease.
The availability of screening methods with sensitivity and specificity close to 100%, combined with complete clinical information prospectively collected, will define the penetrance of each disease and, within a disease, of each genetic variant. This will lead to guidelines for the management of asymptomatic gene carriers based on the predicted risk of becoming symptomatic.
Given the very large number of mutations associated with arrhythmogenic disorders, it may be more realistic to study carefully the larger group of individuals with defects in the same gene rather than attempting to define genotype/phenotype correlations for each mutation. If distinctive features are identified that segregate patients with specific genetic variants of the same disease, gene-specific therapy may result.
The identification of the genetic or environmental factors that modulate the expression of these diseases and understanding the mechanisms whereby relatives with the identical mutation can have radically different clinical histories will also be useful for patient management.
An intriguing aspect of investigating the molecular bases of inherited arrhythmogenic disorders lies in the hope that information provided by studies of relatively rare inherited conditions may help elucidate mechanisms for the acquired variants. The importance of the discovery of the gene for familial atrial fibrillation, for example, will be enhanced if it will lead to an understanding of the causes of the much more prevalent "lone" (and even disease-associated) atrial fibrillation. Similarly, recent data suggest that the acquired LQTS may develop in individuals carrying otherwise apparently "mild" mutations in LQTS-related genes. Polymorphisms of these genes could also predispose to other acquired arrhythmias.
Finally, the step from defective gene function to the clinically manifest arrhythmias involves further complexities related to the environment in which the abnormal proteins exert their function. Further study of the multiple interactions among ion channels, pumps, and exchangers on one hand and the structure and connectivity of the cellular network on the other should improve our understanding of the mechanisms that determine the occurrence of the electrical disturbances that lead to lethal arrhythmias.
|
Acknowledgments |
|---|
We would like to thank Lilly Lehmann-Bircher for her help with the figures. We thank Natalie Pinelli and Valerie Gambier for organizing the logistical aspects of the meeting.
|
Footnotes |
|---|
1 Parts I and II of this article were published in Circulation. 1999;99(4):518–528, February 2 issue. This article is also published in Eur Heart J. 1999;20:179–195. Note, Figures 1 and 2 were published in Circulation. 1999;99(4):518–528, February 2 issue.
2 Participants in the Workshop are listed in the Appendix to Parts I and II. Figures 1 and 2 and References 1 through 94 are also presented in Parts I and II.
|
Appendix 1 |
|---|
|
TopPart III: Molecular Basis...Appendix 1References |
|---|
This article summarizes the outcome of a workshop held at the European Heart House C, Sophia Antipolis, France, October 2–5, 1997. The need for the workshop was proposed by Silvia G. Priori. It was organized by the Study Group on Molecular Basis of Arrhythmias of the Working Group on Arrhythmias of the European Society of Cardiology, and its funding was administered by the Working Group itself. The workshop was cochaired by Silvia G. Priori and André G. Kléber. The final preparation and organization of the manuscript were the responsibility of André G. Kléber, Silvia G. Priori, Dan M. Roden, and Peter J. Schwartz.
Note, References 1 through 94 appear in Parts I and II of this article, published in Circulation. 1999;99:518–528 (February 2 issue).
Received July 15, 1998; revision received October 28, 1998; accepted November 18, 1998.
|
References |
|---|
|
TopPart III: Molecular Basis...Appendix 1References |
|---|
95. Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N, Kangawa K, Matsuo H, Raftery MA, Hirose T, Inayama S, Hayashida H, Miyata T, Numa S. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature. 1984;312:121–127.[Medline] [Order article via Infotrieve]
96.
Deal KK, England SK, Tamkun MM. Molecular physiology
of cardiac potassium channels. Physiol Rev. 1996;76:49–67.
97. Hosey MM, Chien AJ, Puri TS. Structure and regulation of L-type calcium channels: a current assessment of the properties and roles of channel subunits. Trends Cardiovasc Med. 1996;6:265–273.
98.
Roden DM, George A Jr. Structure and function of
cardiac sodium and potassium channels. Am J Physiol. 1997;273:H511–H525.
99. Isom LL, Dejongh KS, Catterall WA. Auxiliary subunits of voltage-gated ion channels. Neuron. 1994;12:1183–1194.[Medline] [Order article via Infotrieve]
100. Adelman JP. Proteins that interact with the pore-forming subunits of voltage-gated ion channels. Curr Opin Neurobiol. 1995;5:286–295.[Medline] [Order article via Infotrieve]
101. Scannevin RH, Trimmer JS. Cytoplasmic domains of voltage-sensitive K+ channels involved in mediating protein-protein interactions. Biochem Biophys Res Commun. 1997;232:585–589.[Medline] [Order article via Infotrieve]
102. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.[Medline] [Order article via Infotrieve]
103. McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, Fishman GI. A minK-HERG complex regulates the cardiac potassium current IKr. Nature. 1997;388:289–292.[Medline] [Order article via Infotrieve]
104.
Yang T, Kupershmidt S, Roden DM. Anti-minK antisense
decreases the amplitude of the rapidly activating cardiac delayed
rectifier K+ current. Circ Res. 1995;77:1246–1253.
105.
Dixon JE, Shi W, Wang HS, McDonald C, Yu H, Wymore RS, Cohen
IS, McKinnon D. Role of the Kv4.3 K+ channel in
ventricular muscle: a molecular correlate for the transient
outward current. Circ Res. 1996;79:659–668.
106.
Tyson J, Tranebjærg L, Bellman S, Wren C, Taylor J, Bathen
J, Aslaksen B, Sørland SJ, Lund O, Malcolm S, Pembrey M,
Bhattacharya S, Bitner-Glindzicz M. IsK and KvLQT1: mutation in either
of the two subunits of the slow component of the delayed rectifier
potassium channel can cause Jervell and Lange-Nielsen syndrome.
Hum Mol Genet. 1997;6:2179–2185.
107. Vetter DE, Mann JR, Wangemann P, Liu JZ, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J. Inner ear defects induced by null mutation of the IsK gene. Neuron. 1996;17:1251–1264.[Medline] [Order article via Infotrieve]
108.
Wang L, Feng ZP, Kondo CS, Sheldon RS, Duff HJ. Developmental
changes in the delayed rectifier K+ channels in
mouse heart. Circ Res. 1996;79:79–85.
109.
Davies MP, An RH, Doevendans P, Kubalak S, Chien KR, Kass RS.
Developmental changes in ionic channel activity in the embryonic murine
heart. Circ Res. 1996;78:15–25.
110.
Lipka LJ, Siegelbaum SA, Robinson RB, Berman MF. An analogue
of cAMP mimics developmental change in neonatal rat
ventricular myocyte sodium current kinetics. Am
J Physiol. 1996;270:H194–H199.
111. Zhang JF, Robinson RB, Siegelbaum SA. Sympathetic neurons mediate developmental change in cardiac sodium channel gating through long-term neurotransmitter action. Neuron. 1992;9:97–103.[Medline] [Order article via Infotrieve]
112.
Yang T, Roden DM. Regulation of sodium current development in
cultured atrial tumor myocytes (AT-1 cells). Am J
Physiol. 1996;271:H541–H547.
113. Kupershmidt S, Yang T, Roden DM. Inhibition of ß-subunit expression prevents development of mature sodium current phenotype in cultured heart cells. Circulation. 1996;94(suppl I):I-287. Abstract.
114.
Malfatto G, Rosen TS, Steinberg SF, Ursell PC, Sun LS, Daniel
S, Danilo PJ, Rosen MR. Sympathetic neural modulation of cardiac
impulse initiation and repolarization in the newborn rat. Circ
Res. 1990;66:427–437.
115.
Zipes DP. Influence of myocardial ischemia and
infarction on autonomic innervation of heart. Circulation. 1990;82:1095–1105.
116.
Abrahamsson C, Palmer M, Ljung B, Duker G, Baarnhielm C,
Carlsson L, Danielsson B. Induction of rhythm abnormalities in the
fetal rat heart: a tentative mechanism for the embryotoxic effect of
the class III antiarrhythmic agent almokalant. Cardiovasc
Res. 1994;28:337–344.
117. Delorme B, Dahl E, Jarry GT, Marics I, Briand JP, Willecke K, Gros D, Theveniau RM. Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system. Dev Dyn. 1995;204:358–371.[Medline] [Order article via Infotrieve]
118.
Delorme B, Dahl E, Jarry GT, Briand JP, Willecke K, Gros D,
Theveniau RM. Expression pattern of connexin gene products at the
early developmental stages of the mouse cardiovascular
system. Circ Res. 1997;81:423–437.
119.
Wang Z, Fermini B, Nattel S. Delayed rectifier outward
current and repolarization in human atrial myocytes. Circ
Res. 1993;73:276–285.
120.
Brahmajothi MV, Morales MJ, Liu S, Rasmusson RL, Campbell DL,
Strauss HC. In situ hybridization reveals extensive diversity of
K+ channel mRNA in isolated ferret cardiac
myocytes. Circ Res. 1996;78:1083–1089.
121. Kupershmidt S, Sutherland M, King D, Magnuson MA, Roden DM. Replacement by homologous recombination of the minK gene with LacZ reveals cell-specific minK expression. Biophys J. 1997;72:A226. Abstract.
122.
Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC,
Di DJ, Gintant GA, Liu DW. Heterogeneity within the
ventricular wall: electrophysiology and pharmacology of
epicardial, endocardial, and M cells. Circ Res. 1991;69:1427–1449.
123.
Strauss HC, Bigger JJ, Hoffman BF.
Electrophysiological and ß-receptor blocking
effects of MJ 1999 on dog and rabbit cardiac tissue. Circ
Res. 1970;26:661–678.
124.
Roden DM, Hoffman BF. Action potential prolongation and
induction of abnormal automaticity by low quinidine concentrations in
canine Purkinje fibers: relationship to potassium and cycle length.
Circ Res. 1985;56:857–867.
125.
Liu DW, Antzelevitch C. Characteristics of the delayed
rectifier current (IKr and
IKs) in canine ventricular
epicardial, midmyocardial, and endocardial myocytes: a weaker
IKs contributes to the longer action
potential of the M cell. Circ Res. 1995;76:351–365.
126.
Dixon JE, McKinnon D. Quantitative analysis of
potassium channel mRNA expression in atrial and ventricular
muscle of rats. Circ Res. 1994;75:252–260.
127.
Näbauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G.
Regional differences in current density and rate-dependent properties
of the transient outward current in subepicardial and subendocardial
myocytes of human left ventricle. Circulation. 1996;93:168–177.
128.
Po S, Roberds S, Snyders DJ, Tamkun MM, Bennett PB.
Heteromultimeric assembly of human potassium
channels: molecular basis of a transient outward current? Circ
Res. 1993;72:1326–1336.
129. Gros DB, Jongsma HJ. Connexins in mammalian heart function. Bioessays. 1996;18:719–730.[Medline] [Order article via Infotrieve]
130.
Anumonwo JM, Wang HZ, Trabka JE, Dunham B, Veenstra RD,
Delmar M, Jalife J. Gap junctional channels in adult mammalian sinus
nodal cells: immunolocalization and electrophysiology. Circ
Res. 1992;71:229–239.
131. Trabka JE, Coombs W, Lemanski LF, Delmar M, Jalife J. Immunohistochemical localization of gap junction protein channels in hamster sinoatrial node in correlation with electrophysiologic mapping of the pacemaker region. J Cardiovasc Electrophysiol. 1994;5:125–137.[Medline] [Order article via Infotrieve]
132.
ten Velde I, de Jonge B, Verheijck EE, van Kempen MJ,
Analbers L, Gros D, Jongsma HJ. Spatial distribution of connexin43, the
major cardiac gap junction protein, visualizes the cellular network for
impulse propagation from sinoatrial node to atrium. Circ
Res. 1995;76:802–811.
133. Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE. Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J Clin Invest. 1997;99:1991–1998.[Medline] [Order article via Infotrieve]
134.
Kanter HL, Laing JG, Beau SL, Beyer EC, Saffitz JE. Distinct
patterns of connexin expression in canine Purkinje fibers and
ventricular muscle. Circ Res. 1993;72:1124–1131.
135.
Luo CH, Rudy Y. A dynamic model of the cardiac
ventricular action potential, I: simulations of ionic
currents and concentration changes. Circ Res. 1994;74:1071–1096.
136.
Fabiato A. Simulated calcium current can both cause calcium
loading in and trigger calcium release from the sarcoplasmic reticulum
of a skinned canine cardiac Purkinje cell. J Gen
Physiol. 1985;85:291–320.
137.
Yue DT, Backx PH, Imredy JP. Calcium-sensitive inactivation
in the gating of single calcium channels. Science. 1990;250:1735–1738.
138.
Sipido KR, Callewaert G, Carmeliet E. Inhibition and rapid
recovery of Ca2+ current during
Ca2+ release from sarcoplasmic reticulum in
guinea pig ventricular myocytes. Circ Res. 1995;76:102–109.
139.
Grantham CJ, Cannell MB. Ca2+ influx
during the cardiac action potential in guinea pig
ventricular myocytes. Circ Res. 1996;79:194–200.
140. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J. 1995;68:949–964.[Medline] [Order article via Infotrieve]
141.
January CT, Riddle JM. Early afterdepolarizations: mechanism
of induction and block: a role for L-type Ca2+
current. Circ Res. 1989;64:977–990.
142.
Janse MJ, van der Steen A, van Dam R. Refractory period of
the dog's ventricular myocardium following
sudden changes in frequency. Circ Res. 1969;24:251–262.
143. Jack JJB, Noble D, Tsien RW. Electric Current Flow in Excitable Cells. Oxford, UK: Clarendon Press; 1975.
144.
Buchanan JW, Saito T, Gettes LS. The effects of
antiarrhythmic drugs, stimulation frequency, and potassium-induced
resting membrane potential changes on conduction velocity and dV/dtmax
in guinea pig myocardium. Circ Res. 1985;56:696–703.
145.
Kléber AG, Riegger CB, Janse MJ. Electrical uncoupling
and increase of extracellular resistance after induction of
ischemia in isolated, arterially perfused rabbit
papillary muscle. Circ Res. 1987;61:271–279.
146.
Riegger CB, Alperovich G, Kléber AG. Effect of oxygen
withdrawal on active and passive electrical properties of
arterially perfused rabbit ventricular muscle.
Circ Res. 1989;64:532–541.
147.
Rudy Y, Quan W. A model study of the effects of the discrete
cellular structure on electrical propagation in cardiac tissue.
Circ Res. 1987;61:815–823.
148. Peters NS. New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischemic and hypertrophied human hearts. Clin Sci. 1996;90:447–452.[Medline] [Order article via Infotrieve]
149.
Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac
tissue: roles of sodium and L-type calcium currents during reduced
excitability and decreased gap junction coupling. Circ Res. 1997;81:727–741.
150. Joyner RW, Kumar R, Wilders R, Jongsma HJ, Verheijck EE, Golod DA, Van GA, Wagner MB, Goolsby WN. Modulating L-type calcium current affects discontinuous cardiac action potential conduction. Biophys J. 1996;71:237–245.[Medline] [Order article via Infotrieve]
151. Weidmann S. Effect of current flow on cardiac muscle. J Physiol (Lond). 1951;115:227–236.
152. Le Grice IJ, Smaill BH, Chai LZ, Edgar SG, Gavin JB, Hunter PJ. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol. 1995;38:H571–H582.
153. Spach MS, Josephson ME. Initiating reentry: the role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol. 1994;5:182–209.[Medline] [Order article via Infotrieve]
154.
Cabo C, Pertsov AM, Baxter WT, Davidenko JM, Gray RA, Jalife
J. Wave-front curvature as a cause of slow conduction and block in
isolated cardiac muscle. Circ Res. 1994;75:1014–1028.
155. Fast VG, Kléber AG. Role of wavefront curvature in propagation of cardiac impulse. Cardiovasc Res. 1996;33:258–271.
156. Fast VG, Kléber AG. Cardiac tissue geometry as a determinant of unidirectional conduction block: assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model. Cardiovasc Res. 1995;29:697–707.[Medline] [Order article via Infotrieve]
157.
Rohr S, Salzberg BM. Characterization of impulse propagation
at the microscopic level across geometrically defined expansions of
excitable tissue: multiple site optical recording of
transmembrane voltage (MSORTV) in patterned growth heart cell cultures.
J Gen Physiol. 1994;104:287–309.
158. Spach MS, Kootsey JM. Relating the sodium current and conductance to the shape of transmembrane and extracellular potentials by simulation: effects of propagation boundaries. IEEE Trans Biomed Eng. 1985;32:743–755.[Medline] [Order article via Infotrieve]
159. Iida M, Kodama I, Toyama J. Negative dromotropic effects of class I antiarrhythmic drugs in anisotropic ventricular muscle. Cardiovasc Res. 1996;31:640–650.[Medline] [Order article via Infotrieve]
160. Rohr S, Kucera J. Involvement of the calcium inward current in cardiac impulse propagation: induction of unidirection conduction block by nifedipine and reversal by K 8644. Biophys J. 1996;72:745–766.
161.
Rohr S, Kucera JP, Fast VG, Kléber AG. Paradoxical
improvement of impulse conduction in cardiac tissue by partial cellular
uncoupling. Science. 1997;275:841–844.
This article has been cited by other articles:
 |
|
 |
|
  M. J. Heradien, A. Goosen, L. Crotti, G. Durrheim, V. Corfield, P. A. Brink, and P. J. Schwartz Does Pregnancy Increase Cardiac Risk for LQT1 Patients With the KCNQ1-A341V Mutation? J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1410 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Weiss, G. Seemann, F. B. Sachse, and O. Dössel Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall Europace, January 1, 2005; 7(s2): S105 - S117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Schwartz Stillbirths, Sudden Infant Deaths, and Long-QT Syndrome: Puzzle or Mosaic, the Pieces of the Jigsaw Are Being Fitted Together Circulation, June 22, 2004; 109(24): 2930 - 2932. [Full Text] [PDF]
|
|
|
|
|
|
F. Gaita, C. Giustetto, F. Bianchi, R. Schimpf, M. Haissaguerre, L. Calo, R. Brugada, C. Antzelevitch, M. Borggrefe, and C. Wolpert Short QT syndrome: pharmacological treatment J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1494 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. KLEBER and Y. RUDY Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias Physiol Rev, April 1, 2004; 84(2): 431 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Shafer, A. S. Habib, and T. J. Gan Safety of Patients Reason for FDA Black Box Warning on Droperidol * Response Anesth. Analg., February 1, 2004; 98(2): 551 - 552. [Full Text] [PDF]
|
|
|
|
 |
|
 K. J Paavonen, H. Chapman, P. J Laitinen, H. Fodstad, K. Piippo, H. Swan, L. Toivonen, M. Viitasalo, K. Kontula, and M. Pasternack Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG) Cardiovasc Res, September 1, 2003; 59(3): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ma, C. Lin, S. Teng, Y. Chai, R. Bahring, V. Vardanyan, L. Li, O. Pongs, and R. Hui Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family Cardiovasc Res, September 1, 2003; 59(3): 612 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gaita, C. Giustetto, F. Bianchi, C. Wolpert, R. Schimpf, R. Riccardi, S. Grossi, E. Richiardi, and M. Borggrefe Short QT Syndrome: A Familial Cause of Sudden Death Circulation, August 26, 2003; 108(8): 965 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yong, X. Tian, and Q. Wang LQT4 Gene: The "Missing" Ankyrin Mol. Interv., May 1, 2003; 3(3): 131 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S Chugh, S. Whitesel, M. Turner, C. T Roberts Jr., and S. R Nagalla Genetic basis for chamber-specific ventricular phenotypes in the rat infarct model Cardiovasc Res, February 1, 2003; 57(2): 477 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X Jouven, A Hagege, P Charron, L Carrier, O Dubourg, J M Langlard, S Aliaga, J B Bouhour, K Schwartz, M Desnos, et al. Relation between QT duration and maximal wall thickness in familial hypertrophic cardiomyopathy Heart, August 1, 2002; 88(2): 153 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]
|
|
|
|
|
|
D. Corrado, C. Basso, and G. Thiene Sudden cardiac death in young people with apparently normal heart Cardiovasc Res, May 1, 2001; 50(2): 399 - 408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Spach Mechanisms of the Dynamics of Reentry in a Fibrillating Myocardium : Developing a Genes-to-Rotors Paradigm Circ. Res., April 27, 2001; 88(8): 753 - 755. [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. O'Brien, M. Apkon, C. I. Berul, H. T. Patel, K. Saupe, M. Spindler, J. S. Ingwall, and R. Zahler Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha 3-isoform in hearts Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2133 - H2142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Burnes, B. Taccardi, and Y. Rudy A Noninvasive Imaging Modality for Cardiac Arrhythmias Circulation, October 24, 2000; 102(17): 2152 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ficker, D. Thomas, P. C. Viswanathan, A. T. Dennis, S. G. Priori, C. Napolitano, M. Memmi, B. A. Wible, E. S. Kaufman, S. Iyengar, et al. Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1748 - H1756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Chugh, K. L. Kelly, and J. L. Titus Sudden Cardiac Death With Apparently Normal Heart Circulation, August 8, 2000; 102(6): 649 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chouabe, N. Neyroud, P. Richard, I. Denjoy, B. Hainque, G. Romey, M.-D. Drici, P. Guicheney, and J. Barhanin Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk Cardiovasc Res, March 1, 2000; 45(4): 971 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. E. Evans and M. V. Relling Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics Science, October 15, 1999; 286(5439): 487 - 491. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||