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Basic Science for the Clinical Electrophysiologist
Cardiac Pacing
From Biological to Electronic . . . to Biological?
Michael R. Rosen, MD; Peter R. Brink, PhD; Ira S. Cohen, MD, PhD; Richard B. Robinson, PhD
Abstract—The prevention and treatment of life-threatening bradyarrhythmias have been revolutionized in the last half
century by electronic pacemakers. Because this represents a palliative therapy, attempts have begun to effect a cure with
the novel tools of gene and cell therapy. Over time, the strategies used have coalesced to focus on achieving a stable
and autonomically responsive cardiac rhythm in a setting that ultimately would require no implanted hardware. In this
report, we review the history of the disease process being treated, approaches now in progress, and the demands that
must be met if biological therapies are to be successful. (Circ Arrhythmia Electrophysiol. 2008;1:54-61.)
Key Words: atrioventricular block 䡲 cell therapy of bradyarrhythmias 䡲 gene therapy
䡲 gene therapy of bradyarrhythmias 䡲 hyperpolarization-activated, cyclic nucleotide-gated channels
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M
atrioventricular conduction were the work of His7 in 1893 and
Tawara8 in 1906. Only Purkinje’s9 work on the false tendons
in 1845 may have been available to Stokes, and this was an
anatomic treatment of the ventricular conducting system.
If one does not know the origin of the heartbeat, where and
how does one start to treat its dysfunction? In fact, the
beginnings of electronic pacemaking anteceded the understanding of the mammalian sinus node and atrioventricular
conduction. It appears that the first to stimulate mammalian
hearts in a systematic fashion was McWilliam10 in 1889. He
used induction shocks, the rate of which was regulated by a
metronome at 60 to 70 bpm to generate pacemaker function
in the ventricles of cats whose sinus rhythm had been
depressed via vagal stimulation. He also emphasized the
potential therapeutic value of the procedure for treating
human subjects and described the type and placement of
electrodes to be used.
Advancement was slow. In Australia in 1928, Lidwell11
reported using an electric power source to deliver shocks
through a needle plunged into the heart to revive “a stillborn
infant.” Hyman12 in Philadelphia used a hand-cranked generator to provide electric shocks in 1932 and coined the term
cardiac pacemaker. The modern era in pacing was ushered in
independently by Hopps et al13 and by Zoll,14 whose devices
were used in the 1950s to deliver transcutaneous shocks.
Weirich et al15 in 1957 brought back the intramyocardial
needle electrode to treat postsurgical complete heart block,
and in that same year Bakken16 fabricated the first portable
external pacemaker.
Temporary transvenous pacing was reported in 195917 and
permitted practitioners to dispense with thoracotomies for
ore than 2 millennia ago, the Chinese physician Pien
Ch’io1 reported what appear to have been variations on
heart block. He wrote that if 1 heartbeat of 50 were dropped,
the patient was normal and had no diseased organs. If the
number increased to 1 in 40, then life expectancy was limited
to 4 years, and a single organ was diseased (which organ was
not specified). As the number of dropped beats increased
further, life expectancy diminished and diseased organs
increased progressively, until, at 1 dropped beat of 3 to 4, life
expectancy was approximately a week.
That was about as good a description of a devastating and
incurable arrhythmia as existed until 1761, when Morgagni
described what later would be referred to as Adams-Stokes
attacks. As quoted by Osler, Morgagni wrote: “My fellow
citizen, Annastasio Poggi, a grave and worthy priest. . .was in
his sixty-eighth year. . .moderately fat and of a florid complexion, when he was first seized with the epilepsy, which left
behind it the greatest slowness of pulse, and in like manner a
coldness of the body. But this coldness of the body was
overcome within seven hours, nor did it return any more,
though the disorder often returned; but the slowness of the
pulse still remained.”2
The separate reports of Adams3 (1827) and Stokes4 (1846)
further detailed the symptoms and presenting signs of patients. They did far less well when it came to therapy. In part,
the perplexity over treatment stemmed from the fact that the
origin and the conduction of the human heartbeat were then
mysteries. The structure and beginning appreciation of the
function of the sinus node as cardiac pacemaker awaited the
work, respectively, of Keith and Flack5 in 1907 and Lewis
and associates6 in 1910. The beginnings of comprehension of
From the Center for Molecular Therapeutics (M.R.R., I.S.C., R.B.R.) and Departments of Pharmacology (M.R.R., I.S.C., R.B.R.) and Pediatrics
(M.R.R.), College of Physicians and Surgeons of Columbia University, New York, NY; and Institute for Molecular Cardiology (M.R.R., P.R.B., I.S.C.)
and Department of Physiology and Biophysics (M.R.R., P.R.B., I.S.C.), Stony Brook University, Stony Brook, NY.
Correspondence to Michael R. Rosen, MD, Center for Molecular Therapeutics, Departments of Pharmacology and Pediatrics, College of Physicians
and Surgeons of Columbia University, 630 W 168 St, PH 7 West-321, New York, NY 10032. E-mail [email protected]
© 2008 American Heart Association, Inc.
Circ Arrhythmia Electrophysiol is available at http://circep.ahajournals.org
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DOI: 10.1161/CIRCEP.108.764621
Rosen et al
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intramyocardial electrode placement.18 Then, the early 1960s
saw fixed-rate pacing via the transvenous route with the use of
permanently implanted power packs. The units were bulky, their
batteries had limited functionality, and their shocks too often
competed with existing idioventricular rhythms. They were life
saving, however. In the 1960s and 1970s, batteries, electrodes,
and software all were improved. The resulting pacemakers
incorporated a demand mode, could sense competing beats, and
could reset to avoid arrhythmogenesis.11,18,19
We now have nearly achieved a pacemaker nirvana:
Atrioventricular (AV) sequential pacing permits the normal
staging of atrial and ventricular contractions in patients with
normal sinus nodes but with AV block. The coronary sinus
permits access to the epicardial veins for biventricular pacing
used in the setting of heart failure. Cardioverter-defibrillators
that sense, shock, and pace when needed are life saving for
patients with potentially lethal tachycardias. As if this were
not enough, units now being used can vary heart rate to adjust
to the exercise level of a patient,20 and leadless electrodes are
being developed that may permit stimulation of the heart
without incorporating a catheter.
Do the units have problems? Yes. These include (1)
unresponsiveness to the autonomic nervous system (to the
demands of exercise and emotion), although variable rate
units are a potential answer to this need; (2) a requirement for
monitoring and maintenance, including at times battery
and/or electrode replacement; (3) infection or interference
from other devices; (4) risk of heart failure evolving with
right ventricular apical placement of electrodes (now being
met by use of other electrode sites); and (5) problems in
adapting equipment to the growth and development of pediatric patients.21,22
Despite these issues, it is highly likely that with continued
effort, electronic pacemakers will be made even better. As a
result of all this, we can say that the electronic revolution has
been astounding, and its future is bright. Why in the world
would anyone want to build a biological pacemaker?
Back to the Future: Why Build a
Biological Pacemaker?
An anecdote: A chief of medicine whom one of us (M.R.R.)
knew had an outstanding peritoneal dialysis unit in his
department. A generous donor offered to bankroll a hemodialysis unit, at the time a new and largely untested therapy.
The chief declined the offer, stating that peritoneal dialysis
was state of the art and was excellent in its outcome, and this
new therapy would likely never work (as well) in any case.
We mention this story because the mistake it highlights is
often repeated. Reviewing medical history reveals a tendency
to the Panglossian—accepting that which is available for
clinical use as “the best” of all possibilities. The best is
usually the product of a sequence originating in imagination
and running through planning, obtaining materials, seeking
proof of concept, and testing for success/failure. Regardless
of what the best is at any time, the question that should arise
is: Can we do better?
In light of the above, why now build a biological pacemaker? The answer is not because the electronic units are
bad; they are as good as can be made right now and will only
Biological Pacing
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be made better. One decides to build a biological pacemaker
because one has the imagination, the beginning tools, the will,
and the possibility that maybe, just maybe, one can recreate
the normal function of the heart using entirely biological
materials. Would that confer an advantage over electronics?
Arguably, the answer is affirmative if we could construct a
unit that does the following: (1) competes effectively in
head-to-head competition with electronic pacemakers yet
requires no battery, no electrodes, and no replacement; (2) not
only creates a lifelong, stable physiological rhythm but also is
responsive to the autonomic nervous system and as such to
the demands of exercise and emotional status; (3) is implantable at a site that optimizes the pathway of cardiac (or at least
ventricular) activation, such that contraction and cardiac
output are similarly optimized; and (4) does not induce
proarrhythmia or carry concerns about inflammation, infection, or neoplasia. In other words, the ultimate aim is to cure
rather than merely palliate.21,22 And it is by curing, perhaps
only by curing, that the biological unit can achieve superiority. In this case, there would be no electrodes, no batteries, no
power packs, no software. Would any of us seriously argue
the superiority of reclaiming normal function over the use of
a prosthesis, regardless of how sophisticated that prosthesis
might be?
Although this is a tall order and may take years to realize,
if one wishes to advance beyond an outstanding therapy such
as electronic pacing, one needs to aim for perfection. Such
perfection need not be achieved at the outset: At such time as
biological units become useful adjuncts to electronics, this
would suffice for beginning their testing. As shall be summarized in the discussion of tandem pacing, this level of
achievement may not be that far away.
Building a Biological Pacemaker: What is the
Template? What Are the Outcomes?
The template for most of us working in this area is the
sinoatrial node. The goal is not necessarily replicating the
node structurally and functionally but replicating enough of
its function to provide an effective mime. As reviewed in
Figure 1,23 the sinus node depolarizes spontaneously during
phase 4 until membrane potential reaches threshold and an
action potential is generated. This event occurs rhythmically
and regularly for the lifetime of most individuals. The slope
of phase 4 depolarization results from a balance between
inward and outward ion currents. The initial inward current,
activated on hyperpolarization of the membrane at the end of
repolarization, is referred to as If.23,24 Other currents that are
inward and contribute to phase 4 depolarization are the T- and
L-type Ca currents (the latter largely responsible for the
upstroke of the sinus node action potential).23 Providing
outward current during the same time frame are the not yet
completely decayed potassium currents IKr and IKs and a weak
IK1.23 In addition, the Na–Ca exchanger operates during phase
4 to further influence the rate of depolarization of the
membrane.25
Modulating the ion channel contribution to pacemaker
function is the autonomic nervous system.23 Catecholamine
binding to ␤-adrenergic receptors operates via a Gs protein–
linked pathway to increase cyclic adenosine monophosphate
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Strategies that have been used to generate biological
pacemaker function are based on gene and/or cell therapy and
are as follows.
Gene Therapy
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Figure 1. A, Representation of sinoatrial node action potential
(control, solid lines) and some of the ion channels and exchangers contributing to it. If is activated on hyperpolarization, providing inward current initiating phase 4. T-type and L-type Ca currents are initiated toward the end of phase 4. The latter also
contributes the major current to the action potential upstroke.
Na-Ca exchange current also influences the phase 4 slope.
Delayed rectifier current IK is responsible for repolarization. The
acceleratory effects of norepinephrine (NE) are represented as
broken lines. A prominent increase in phase 4 reflects the
actions of norepinephrine on If. B, An HCN (hyperpolarizationactivated, cyclic nucleotide– gated) pacemaker channel. There
are 6 transmembrane spanning domains. When the channel is in
the open position, Na is the major ion transmitted. cAMP binding sites are present near the carboxy terminus. ␤1-Adrenergic
(␤1-AR) and M2-muscarinic receptors, which provide norepinephrine and acetylcholine (ACh) binding sites, respectively, are
shown. Via G-protein coupling, these receptors regulate adenylyl cyclase (AC) activity, which in turn regulates intracellular
cAMP levels, determining the availability of the second messenger for binding and channel modulation. Adapted from Biel et
al23 with permission from Elsevier Limited. Copyright 2002
Elsevier Limited.
(cAMP) synthesis and increase pacemaker rate, whereas
acetylcholine binding to M2 muscarinic receptors operates
via a Gi protein–linked pathway to reduce cAMP synthesis,
which reduces rate. cAMP is critical to pacemaker rate
because of its action on the HCN (H for hyperpolarization
activated, CN for cyclic nucleotide gated) channels that
determine If function, as will be described below.
When one considers the above, it should be understood that
none of the ion currents described is uniquely responsible for
pacemaker activity. All contribute, and marked alteration in
any one can be balanced by altered function of the others,
such that pacemaker activity persists, albeit at different rates.
This redundancy in function is important to maintain the
initiation and sustenance of the heartbeat under a variety of
circumstances. A good example is the effect of the If-blocking
drug ivabradine on sinoatrial rate: The latter may decrease by
as much as 30%, accounting for the therapeutic effect of the
drug, but effective pacemaker function is preserved.26 Moreover, all currents contribute in such a way to permit the
generalization that any event that increases inward current
and/or decreases outward current will increase pacemaker
rate.
Gene therapies either overexpress a gene that will increase
pacemaker rate in cardiac myocytes (by increasing inward
current) or knock out the function of a gene that would
otherwise decrease pacemaker rate (and decrease outward
current). These approaches modify the electric signals generated by cardiac myocytes and/or specialized conducting cells
to transform them into dominant pacemakers. The modified
current, in concert with the endogenous “package” of ionic
currents in a myocyte or specialized conducting fiber, creates
a pacemaker in a cell that previously had little or no
pacemaker function.
The first biological pacemaker created was based on
overexpression of ␤2-adrenergic receptors in porcine atrium.27 The result was an increase in basal atrial rate as well as
responsiveness to catecholamine. While providing proof of
concept that biological pacing might be workable, this approach also carried the potential proarrhythmic complications
of excess catecholamine action on the heart. The first attempt
to manipulate ion channel activity was performed by injecting
a dominant negative construct of the repolarizing K current
IK1 into guinea pig ventricle.28 This resulted in an increased
automatic rate in situ, as well as increased phase 4 depolarization in isolated myocytes. However, reducing repolarizing
K current also leads to prolonged repolarization, as was
reported subsequently by the same authors.29 This outcome is
potentially arrhythmogenic.
The other ion channel approach that has been explored and
largely adopted by most groups now working in the area is to
increase or to create a variant on the inward current If.30,31
Because this approach now holds center stage, some additional explanation of the ion channels that generate If will be
provided. If is carried by any of 4 isoforms of the HCN
channel.23 Isoforms 1, 2, and 4 reside in heart, and isoform 3
resides in brain. Common to all isoforms is that the channel
opens on hyperpolarization of the membrane to admit inward
Na current, a property central to the development of pacemaker function. The channel also closes rapidly on depolarization. These characteristics of opening and closing of the
channel are important to the avoidance of proarrhythmia
because inward current is generated during phase 4 alone and
not during phase 2 or 3 of repolarization. As a result, there is
no action potential prolongation that might lead to
proarrhythmia.
All HCN isoforms have cAMP binding sites near the
carboxy terminus of the channel. The binding of cAMP to
these sites shifts activation positively, resulting in a faster rate
of phase 4 depolarization.23 This interaction with cAMP is
responsible for the autonomic control of the aforementioned
pacemaker current.
To date, the use of HCN2 and HCN4 to fabricate biological
pacemakers has been reported, with most work having been
done with HCN2. In addition, mutant and chimeric channels
have been reported. Two viral vectors have been used in the
gene therapy experiments. The first is adenovirus, which is
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Figure 2. Rationale for building a biological pacemaker. Top, Initiation of spontaneous rhythms by sinoatrial (SA) node cells. Here,
action potentials (inset) are initiated via inward current flowing through transmembrane HCN channels. These open as the membrane
repolarizes toward its maximum diastolic potential and close when the membrane depolarizes during the action potential. Current flowing via gap junctions to adjacent myocytes results in their excitation and the propagation of impulses through the conducting system.
Bottom, A stem cell engineered to incorporate HCN channels in its membrane. These channels can only open and carry inward current
when the membrane is hyperpolarized. This hyperpolarization can be delivered if an adjacent myocyte is tightly coupled to the stem
cell via gap junctions. In this setting, the opening of the HCN channels induces local current flow to excite the adjacent myocyte and
initiate an action potential that propagates through the conducting system. The depolarization of the action potential will result in the
closing of the HCN channels. Hence, the stem cell–myocyte pairing has 2 cells working as a single functional unit whose operation
depends on the gap junctions that form between the 2 cell types. From Rosen et al21 with permission from Elsevier Limited. Copyright
2004 European Society of Cardiology.
expressed episomally only and is useful for proof-of-concept
studies lasting 2 to 4 weeks at most. The second is lentivirus,
which is incorporated in cells genomically; although it is slow
to express, it should be permanent in expression for the life of
the cell.
HCN2 in an adenoviral construct expresses well in atrium31
and ventricle.32 When injected into the left atrium, it generated pacemaker function that was sensitive to both catecholamines and vagal stimulation, increasing and decreasing the
rate, respectively.31 When injected into the left ventricular
specialized conducting system of dogs whose sinus rate
and/or AV conduction was suppressed by vagal stimulation32
or in dogs having AV block secondary to radiofrequency
ablation of the AV nodal region,33 the result was an escape
pacemaker that fired at ⬇50 to 55 bpm in the resting state.
This was responsive to catecholamine infusion such that rate
could increase to ⬇90 bpm. No attempt was made to infuse
acetylcholine, but preliminary experiments on heart rate
variability suggested both a vagal and a sympathetic component to the function of this biological unit.34
Attempts to influence the rate of biological pacemakers by
creating mutant or chimeric channels have met only modest
success. The E324A mutation of HCN2 resulted in increased
catecholamine sensitivity in biophysical studies but showed
no physiologically relevant difference in effect from the
wild-type channel, HCN2.33 An HCN212 chimera incorporating the pore-forming unit of HCN1 (which has more
favorable activation kinetics than HCN2) and the amino and
carboxy termini of HCN2 (which has more robust cAMP
responsiveness than HCN1) resulted in an “overshoot” of
function, in that ventricular tachycardias well over 220 bpm
in rate were the result.35 A mutation of a K channel to give it
the inward current– carrying capability of HCN2 has been
reported,36 but this has no cAMP-binding capacity and, with
this, no potential for autonomic responsiveness. Therefore,
although it is clear that mutating wild-type channels and
creating chimeras and artificial channels result in phenotypic
expression,33,35–37 the right combination of characteristics to
provide a basal heart rate of 60 to 70 bpm and autonomic
responsiveness capable of reaching ⬇150 bpm has not yet
been reported.
Cell Therapy
Because viral vectors for gene therapy can carry various risks
(with the greatest concern being the transmission of viralbased illnesses), other means of creating biological pacemakers have been sought. One approach uses human embryonic
stem cells (hESCs) that are placed in cell culture and “forced”
into a pacemaker lineage.38 The other approach uses adult
human mesenchymal stem cells (hMSCs)39,40 or other cell
types41 as platforms for delivering HCN genes.
Human Embryonic Stem Cells
hESCs coaxed into a pacemaker lineage have the advantage
of not requiring the overexpression of pacemaker genes.
Rather, they have a full complement of these. When injected
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Figure 3. A and B, Biological pacemaker function in canine heart in situ. Top to bottom, ECG leads I, II, III, AVR, AVL, and AVF. A
shows a control that received a saline injection, and B shows an animal that received hMSCs loaded with HCN2 and green fluorescent
protein (GFP). Left panels, Pacing from hMSC injection site showing ECG configuration. Center panels, Spontaneous (Spont.) rhythms
about a week later. In saline, the QRS configuration is independent of impulses initiated at the injection site, and rate is low. In
hMSCs⫹HCN2, the rhythm pace-maps to site of injection, suggesting that it is initiated at the injection site. Right panels, Last 2 beats
of overdrive pacing (shaded) at 80 bpm followed by escape rhythm. Escape time is 4 seconds in saline and 1.3 seconds in
hMSC⫹HCN2. Adapted from Potapova et al39 with permission of Lippincott Williams & Wilkins. Copyright 2004 American Heart Association. C, hMSCs 6 weeks after left ventricular anterior wall intramyocardial injection. Hematoxylin-eosin (H&E) identifies basophilic cells.
These are CD44 positive, reflecting human origin, and GFP positive (via peroxidase stain). These findings indicate that they are, in fact,
the cells we injected 6 weeks earlier. These hMSCs do not display labeling/binding of canine IgG to their surface, evidence against
humoral rejection. CD3-positive T lymphocytes are rarely noted in association with clusters of hMSCs, evidence against cellular rejection. Staining is negative for activated caspase-3, evidence against apoptosis. Magnification ⫻400. Reproduced from Plotnikov et al40
with permission of Lippincott Williams & Wilkins. Copyright 2007 American Heart Association.
into the ventricles of pigs in complete heart block, these
hESCs have delivered acceptable pacemaker function for
several months.38 The cells have coupled with the porcine
myocytes such that the signal transfer from hESCs to the
heart has been robust. One problem has been the need for
immunosuppression of the animals (and this is a general
problem with hESCs). Other issues have been the general
concern that hESCs might eventually evolve into an inimical
cell type (including the possibility of neoplasia) or even into
a cardiac cell that does not persist in having good pacemaker
function, such as a ventricular myocyte.
Human Mesenchymal Stem Cells
As opposed to hESCs, the multipotent hMSCs do not have the
machinery to generate a cardiac action potential; the necessary ion channel components are not present. Present, however, is a robust population of connexins (Cx43 and Cx40)
that are the protein building blocks of gap junctions that
provide the low-resistance pathways for current to flow
among cells.42 These properties led us to hypothesize that (1)
hMSCs might couple electrically to one another and to
myocytes (they do with great efficiency); (2) electroporation
could be used to overexpress HCN2 in hMSCs (the cells
loaded well, obviating the need for viral vectors); and (3) an
hMSC would be hyperpolarized by any repolarizing myocyte
to which it is electrically coupled. This hyperpolarization
would generate inward current that initiates depolarization
and an action potential in the myocyte. In that way, the 2 cells
would constitute a single functional unit, with the hMSC
providing the depolarizing stimulus and the myocyte the
action potential (Figure 2).21,22
hMSCs have been injected into the anterior left ventricular
walls of dogs in complete heart block and have been studied
through 6 weeks (Figure 3).40 Because there is evidence that
hMSCs are immunoprivileged43,44 and are not necessarily
rejected across species, these experiments were done without
immunosuppression. The experiments were successful, showing pacemaker firing at ⬇50 to 60 bpm in these animals
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Figure 4. Tandem pacing. A, A dog with an adenoviral HCN2 construct in the proximal left bundle branch and an electronic pacemaker
with electrode implanted in right ventricular endocardial apex and in complete heart block induced by radiofrequency ablation. Note
that the animal is being paced biologically; the electronic unit then intervenes, and the biological unit then takes over. B summarizes
results from 7 dogs. Those animals receiving electronic pacing have ⬎80% of beats initiated electronically. In contrast, those with tandem pacing see only 30% to 40% of beats as electronically initiated. C, Electroanatomic mapping of left ventricle in a dog with complete heart block, an electronic right ventricular apical endocardial pacemaker, and an HCN2 adenoviral construct administered into the
proximal left bundle branch. Panels demonstrate 4 projections, showing early (red) through late (blue) activation. Left panels show an
impulse activating left ventricular endocardium at several sites simultaneously, reflecting arrival of an impulse initiated in the left bundle
branch system. Right panels show early activation of left ventricular septum via the electronic pacemaker. AP indicates anteroposterior;
LAO, left anterior oblique; RL, right lateral; and PA, posteroanterior. Adapted from Bucchi et al33 with permission of Lippincott Williams
& Wilkins. Copyright 2006 American Heart Association.
(Figure 3A, 3B) as well as catecholamine responsiveness.
Preliminary studies have shown little vagal response, but this
likely reflects the absence of significant vagal innervation of
the ventricular myocardium. Concerns with regard to hMSCs
are a variant on those for hESCs: Will they become an
inimical cell type? Will they stay in place or migrate
elsewhere? What will be their longevity when injected into
the heart? All of these issues remain to be resolved.
Where Do We Stand, and What Is
the Future?
We and others have obtained sufficient evidence from both
viral and stem cell approaches to state that proof of concept
has been demonstrated. We also have evidence that trials can
be designed that permit us to test biological versus electronic
pacemakers in relative safety in patients who are protected
from failure of the biological unit (see reservations below,
however). The likely way to proceed clinically when ready
(perhaps in a patient population with chronic atrial fibrillation
and complete heart block) would be to implant both a
biological pacemaker and an electronic demand pacemaker in
the same individual. The design used here is referred to as
tandem pacing.
We have tested this in dogs in complete heart block to
which we delivered an adenoviral HCN2 construct (into the
left bundle-branch system) and an electronic demand unit, the
electrode of which was placed in the right ventricular endocardial apex (Figure 4).33 The biological pacemaker fired
⬇70% of the time and was catecholamine responsive. Moreover, when the biological unit slowed, the electronic unit took
over seamlessly; similarly, the electronic unit sensed the
biological unit well and discontinued its function when the
biological function emerged.
Extrapolating this tandem system to the clinic, one can
envision a situation in which the biological pacemaker
provides the majority of beats to the heart, conserving the
battery of the electronic unit, and is autonomically responsive, adding this component of function to the patient’s heart.
Via placement at a site in the conducting system that
maximizes cardiac output, the biological unit provides another benefit not seen with electronics to date. At the same
time, the memory function of the electronic unit can track the
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function of the biological unit, providing a record for the
cardiologist.
Issues for the future go well beyond learning how to test
biological versus electronic units. More pressing problems
include understanding whether the biological approach is in
fact superior to the electronic pacemaker in terms of adaptability to the body’s physiology and duration of effectiveness;
the long-term incidence of inflammation, infection, rejection,
and neoplasia; the long-term proarrhythmic potential; the
issue of whether there is localization versus migration of the
viral vector or cells administered; and, for stem cells, the
persistence of administered cell types versus their differentiation into other cells. In addition, other toxicities, not yet
conceived of, must be watched for, and delivery systems must
be optimized.21,22 All of these issues must be laid to rest
before one passes judgment on clinical application.
An additional issue must be considered. Biological pacing
came on the scene as a disruptive technology. In an era of
excellence in electronic pacing, its goal was and remains to
supplant this with a biological alternative. Given the imperfections that still reside with electronics, the possibility of a
system with no wires, no hardware, and a software that is of
the body’s own ion channels and autonomic nervous system
offers something more appealing, if it can be made to
function at the level needed and for the time required.
Nevertheless, the biological approach does not arrive at a
time when electronics are static. As mentioned above, rate
responsiveness is here, and improved and leadless systems
have arrived as well. Therefore, we see 2 competitive
approaches evolving. Which one wins out, traditional electronics upgraded to achieve still newer levels of success or
biologics, is frankly irrelevant. What is important in this, as in
all areas of competition, is that the better approach be identified
and brought to bear to the benefit of the patient in need.
Acknowledgments
The authors express their gratitude to Eileen Franey for her careful
attention to the preparation of the manuscript.
Sources of Funding
Certain of the studies referred to were supported by US Public Health
Service–National Heart, Lung, and Blood Institute grant HL-28958
and by Boston Scientific.
Disclosures
The authors receive research support from Boston Scientific.
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Cardiac Pacing: From Biological to Electronic … to Biological?
Michael R. Rosen, Peter R. Brink, Ira S. Cohen and Richard B. Robinson
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Circ Arrhythm Electrophysiol. 2008;1:54-61
doi: 10.1161/CIRCEP.108.764621
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