Expert Answers to Three Key Questions · PDF file · 2017-03-30may offer the most...

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Dialogues in Cardiovascular Medicine - Vol 11 . No. 1 . 2006

Editorial D. J. Hearse, R. Ferrari 3

Lead Article The control of heart rate: the physiology of the sinoatrial node and the role of the If currentM. J. Shattock, M. R. Rosen 5

Expert Answers to Three Key Questions Can If inhibition help in angina? - J. S. Borer 21

Can If inhibition help in congestive heart failure? - L. Tavazzi, A. Mugelli 30

Can If inhibition help after myocardial infarction? - G. Martin, J. C. Tardif 36

Fascinoma Cardiologica Icons of Cardiology: Maude Elizabeth Abbott: bringing order to congenital malformations of the heart - A. M. Katz 43

Summaries of Ten Seminal Papers - J. C. Hancox, A. F. James 49

What If?

Membrane currents in the rabbit sinoatrial node cell studiedby the double microelectrode method – A. Noma, H. Irisawa

How does adrenaline accelerate the heart? – H. F. Brown and others

Functional and morphological organization of the rabbit sinusnode – W. K. Bleeker and others

Acetylcholine activation of single muscarinic K+ channels inisolated pacemaker cells of the mammalian heart – B. Sakmann

and others

Retarding effect of lowered heart rate on coronary atherosclerosis – P. A. Beere and others

Mechanism of beneficial effect of beta-adrenergic blockade onexercise-induced myocardial ischemia in conscious dogs B. D. Guth and others

Muscarinic modulation of cardiac rate at low acetylcholineconcentrations – D. DiFrancesco and others

Molecular characterization of the hyperpolarization-activatedcation channel in rabbit heart sinoatrial node – T. M. Ishii and

others

The hyperpolarization-activated channel HCN4 is required forthe generation of pacemaker action potentials in the embryonicheart – J. Stieber and others

Long-term prognostic value of resting heart rate in patients withsuspected or proven coronary artery disease – A. Diaz and others

Bibliography of One Hundred Key Papers 61


3

David J. Hearse, BSc, PhD, DSc

Roberto Ferrari, MD, PhD

n 1979, Brown, DiFrancesco and Noble reported in

Nature a sinoatrial current that was so unusual they

felt compelled to christen it the "funny" current (If).

The funny thing about this current, which is gener-

ated by the inward movement of sodium and potassium

ions, is that is activated by hyperpolarization of the cell membrane. Some experts

argued that this current might play a key role in the control of pacemaker activity, while

other experts treated this claim with some suspicion, pointing out that it was a very

small current and only one of the 10 or more

currents responsible for the propagation of

the nodal action potential. It certainly

seemed an unlikely that If might represent

a therapeutic target in the battle against

cardiovascular disease. However, nowadays,

as explained by Michael J. Shattock and Michael R. Rosen, this curious little channel

is known to be able to exert a substantial effect upon heart rate such that its chemical

inhibition may reduce cardiac rate by as much as one fifth without altering the profile

of the action potential or the inotropic state of the ventricle.

Interest in the possible beneficial effects of reducing heart rate had its origins in studies,

also reported in the late 1970s, that demonstrated strong linear relationships between

life span, body mass, metabolic rate, and heart rate. This work culminated in a classical

paper, published in 1997 by Herbert Levine, showing in mammals an inverse semi-

logarithmic relation-ship between heart rate and life expectancy (see Figure, next page).

Levine’s observation raised the alluring possibility of extending life by cardiac slowing.

However, as is very clear from the Figure, man appeared to be an exception in this

otherwise striking relationship, boasting a life span far greater that that predicted from

human heart rate—a phenomenon that might be explained on the basis of the medical

and scientific benefit enjoyed by mankind. At present, there is no definitive evidence

that reducing heart rate in healthy individuals either by exercise or by drugs results in

Editorial

I

•••

pace.mak.er (pas´ ma´ ker), n.a person or thing that sets the pace as inracing; a specialized tissue that governs arhythmic or cyclic biological activity

fun.ny (fun´e), adj.causing amusement,warranting suspicion,curious, impertinent

an increase in longevity. Although ardent runners might believe that spending 5% of

their waking hours acquiring a jogging-induced bradycardia will result in an extended

life span, the evidence is just not there, and, in any event, it is perhaps of questionable

benefit if they only live 2% longer! By contrast, there is clear evidence that reducing

heart rate is associated with an improved survival in a variety of pathologies including

cardiovascular disease, and this presents a fascinating therapeutic possibility that is

explored in this issue of Dialogues. To this end, the superb fail-safe electrical design

of the sinoatrial node, together with the advent of If inhibitors that reduce heart rate

within a tightly controlled range, should provide a means to test more thoroughly the

above associations and perhaps allow us to use our lifetime allocation of 25�108 heart

beats most productively.


Editorial - Hearse and Ferrari

4

Life expectancy (years)

He

art

rate

(b

eats

/min

)

1000

50

20

300

100

1

0 20 40 60 80 100

Mouse

Rat

CatDog

Giraffe

Horse

Elephant

TigerAss

Lion

Whale

Whale

Man

Marmot

Monkey

Hamster600

Relationship between resting heart rate and life expectancy inmammals, according to size.

Reproduced from: Levine HJ.Rest heart rate and life expectancy.J Am Coll Cardiol. 1997;30:1104-1106. Copyright © 1997,Elsevier Biomedical.

•••

We are all born with a finite number of heart beats:I, for one, am not going to waste mine on exercise

Dr A. Glenn Morrow(attributed by Dr J. Borer)

Afundamental feature of the mammalian heartis its ability to maintain rhythmic contractionsin the absence of external stimulation. Themammalian heart contains a myogenic, or

muscle-derived, pacemaker, the sinoatrial node (SA)—a small, but complex, conglomeration of specializedtissue located in the outer reaches of the right atrium.The impulses arising from the pacemaker both deter-mine the heart rate and provide a target for its physio-logical and pharmacological modulation. The nodecontains a mixture of nodal cells, connective tissueand atrial cells, and an understanding of the complexinterplay between these tissues is essential for under-standing how the node works. The specialized nodalcells are themselves not homogeneous—cells fromthe center of the node being both morphologically andelectrophysiologically different from more peripheralcells. However, the defining feature of the nodal cellsthemselves is that they show inherent pacemaker ac-tivity—that is, their diastolic membrane potential isnot stable, but gradually depolarizes to a thresholdfrom which a new action potential is triggered. The ioniccurrents present during this pacemaker depolarization


The control of heart rate: the physiology of thesinoatrial node and the role of the If currentMichael J. Shattock*, PhD; Michael R. Rosen†, MD, PhD *Cardiovascular Division - King’s College - London - UK†Gustavus A. Pfeiffer Professor of Pharmacology - Columbia University - New York, NY - USA

A heart will beat approximately 25�108 times duringthe course of a human being's life. The observationthat most mammals share the same number of heartbeats per lifetime, be it a mouse (600 bpm for 2 years)or a giant tortoise (6 bpm for 200 years), has ledpeople to suggest that if we slowed our heart rate wemight live longer! While there may not be a causalrelationship in fit healthy animals, there is an im-pressive literature accumulating suggesting that thereis a clear and strong association between a lower heartrate and improved prognosis in a variety of diseases.It is, of course, in cardiovascular disease where theslowing of heart rate with specific bradycardic agentsmay offer the most advantage. The question as towhether If inhibition can specifically improve morbid-ity and life expectancy in cardiovascular disease isone we only recently have had the tools to answer, andthe introduction of ivabradine into the armamentari-um offers a unique opportunity to address this ques-tion. We will know a lot more when the BEAUTIFULtrial (MorBidity-mortality EvAlUaTion of the If in-hibitor ivabradine in patients with coronary diseaseand left ventricULar dysfunction) concludes in De-cember 2007.

Keywords: sinoatrial node; heart rate; pacemaker; ion current; action po-tential; HCN channel; ivabradineAddress for correspondence: Prof Michael J. Shattock, CardiovascularDivision, King's College, St Thomas’ Hospital, London SE1 7EH, UK(e-mail: [email protected])

Dialogues Cardiovasc Med. 2006;11:5-17

SELECTED ABBREVIATIONS AND ACRONYMS

BEAUTIfUL MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients withcoronary disease and left ventricULar dysfunction

HCN hyperpolarization-activated cyclic nu-cleotide-gated cation channel

SA sinoatrial (node)

5Copyright © 2006 LLS SAS. All rights reserved www.dialogues-cvm.org

phase are many (at least 10 have been identified) andthis provides levels of redundancy to the function ofthe node that make it very hard to stop. Nodal cellsalso have one other significant feature—they do nothave the large time-independent background potassi-um current (IK1) that is present in ventricular cells. Thisgives the nodal cell a high-input impedance, which,in short, means small currents can exert big effects!Perhaps one of the most important of these small cur-rents is the hyperpolarization-activated inward cur-rent—If.If is the target for adrenergic and cholinergicmodulation of heart rate: agents that increase If accel-erate heart rate and those that inhibit If slow heart rate.This article reviews the physiology of the SA node and,in particular, the importance of If in the regulation ofheart rate. Understanding the physiology of the SA nodeallows the understanding of how such a small currentcan exert a significant effect on heart rate and theseemingly contradictory observation that even completeblockade of this current is safe and will only slow heartrate by about 30%.

EXTRINSIC VS INTRINSIC PACEMAKERS

What can we learn from evolution?

As evolution progressed from simple single cells tocomplex multicellular organisms with discrete special-ized tissues, the need for an efficient circulatory systemdeveloped in parallel. Simple invertebrates such asthe brachiopods (clam-like shellfish) and ascidians (seasquirts) circulate rudimentary blood-like substancesaround open body cavities aided by inefficient peri-staltic "tube" hearts.1 Higher invertebrates such as thedecapods (lobsters) and the cephalopods (octopi, etc)evolved more complex multichambered hearts thatrequire synchronization, coordination, and rhythm (forreview see reference 1). To generate the rhythm, natureexperimented with two different strategies: (i) extrinsicneuronally derived pacemakers; or (ii) intrinsic special-ized muscle tissue. The intrinsic myogenic pacemakersare actually both evolutionarily ancient and wide-spread—being present in most molluscs, insects, andall vertebrates (apart from the lamprey). Myogenichearts have their own intrinsic muscle-derived pace-maker, continue to beat when isolated, and contractsequentially with the wave of contraction spreadingmonotonically from one point to another. Neurogenichearts are found in the annelids (segmented worms),crustaceans, and arachnids (spiders), receive theirpacemaker commands from an extra-cardiac source(the cardiac ganglion), stop when isolated, and all

parts of the heart tend to contract simultaneously. Both neurogenic and myogenic pacemakers have theiradvantages and disadvantages. Neurogenic hearts pro-vide instant control, but are easy to stop. The simul-taneous contraction of a neurogenic heart works wellin a tube heart, but poorly in a multichambered heart.Myogenic pacemakers, conversely, are very hard tostop, but require complex and slow regulation via cir-culating factors from both endocrine and paracrinesources. The wave-like propagation of contraction inthe myogenic heart has mechanical advantages for asingle chamber, but does not easily allow for synchro-nization and coordination between chambers.

While the mammalian pacemaker is essentially myo-genic, rather than choosing between these two evolu-tionary blueprints, the mammalian heart has incorpo-rated the best features of both systems.

The pacemaker of the mammalian heart: a functional mix?

The primary pacemaker of the mammalian heart is theSA node, which consists of specialized myocardial tis-sue (ie, is "myogenic")(see Boyett et al2 for review).Excitation spreads from the node via the atrial musclebefore arriving at the atrioventricular node. Here theimpulse is first delayed and then moved rapidly throughthe specialized "neuronal-like" conduction pathways("neurogenic") of the bundle of His and Purkinje fibersystem before spreading in a propagated wave ("myo-genic") through the myocardium from apex to base. In this way, the mammalian pacemaker generates arobust myocardially derived pacemaker, its more or-ganized or "neuronal-like" propagation allows for thenecessary coordination of contraction of a multicham-bered heart, and, within chambers, the contractionwave favors ejection by spreading toward the outflowtracts of the respective chambers.

LOCATION AND STRUCTURE OF THEMAMMALIAN SINOATRIAL NODE

Gross anatomy

The SA node is a small tear-drop shaped cluster ofspecialized tissue located in the right atrium at thejunction of the superior vena cava, the inferior venacava and, the crista terminalis (Figure 1).3 In man, es-timates of the size of the node vary from 7 to 20 mmin length4,5 and, in the rabbit, 2 to 4 mm in diameter� 6 to 8 mm in length.3 The mammalian SA node is aheterogeneous mixture of specialized nodal cells (which


The physiology of the SA node and the role of If - Shattock and Rosen

6

are themselves by no means homogeneous), atrialmyocytes and a surprisingly large amount of connectivetissue (Figure 1). The amount of connective tissuewithin the node varies with species4 and age,6 but canmake up between 50% and 90% of the node. It is nowclear that both the preponderance of connective tissueand the mixture of other excitable tissues within the SAnode are fundamentally important to normal function.2

The location of the leading pacemaker site in the rab-bit SA node is shown in Figure 1 and the isochronesshow the propagation of the wave of excitation awayfrom its site of initiation.2 Contrary to the schematicsin most textbooks, the wave of excitation actuallyspreads anteriorly and obliquely (towards the top leftof Figure 1 ) towards the crista terminalis, which itmeets as a broad wave front before turning and heading

around and down towards the atrioventricular node.2

Figure 1 also shows a region of low conductance (theblock zone), which is located close to the leadingpacemaker site and provides a region of conductionblock preventing excitation from spreading premature-ly towards the septum. This anatomical arrangementand the circuitous "up and around" excitation exit path-way from the node may confer physiological advan-tages by: (i) ensuring the wave of atrial contractionspreads from the very top of the chamber forcing blooddown towards the atrioventricular valve; and (ii) theblock zone may then prevent reentry of electrical exci-tation from the atrium back into the node.

Microanatomy

The specialized nodal tissue is itself heterogeneous(Figure 2, next page).3,7 Close to the center of the node,the cells are small (5 to 10 µm in diameter and 25 to30 µm long), spindle-shaped, poorly differentiated,contain few myofilaments or mitochondria, and havehighly convoluted membranes containing many caveo-lae (Figure 2A). In short, central nodal cells are simplyempty membranous bags containing few specializedstructures. These central nodal cells (sometimes calledP cells) are the site of the primary pacemaker. Movingoutward away from the center of the node, in mostspecies there is a gradual transition with cells becom-ing larger, having a clear myofilament structure, andcontaining more mitochondria (Figure 2B) the closeryou get to the periphery of the node.2,3,7 Interspersedwithin the node are a third type of nodal cell termed"spider cells," which are seen when the node is disag-gregated into its component parts (Figure 2).7 The roleof these spider cells is uncertain, but clearly their ex-tensive "dendritic" structure and their large surface-vol-ume ratio may suit them to influence the propagationof the electrical wave within the microdomains of thenode and to facilitate electrical coupling between adjacent areas.



7

1 mm

Position of leading pacemaker

Nodal cells Mixed tissue

Block zone

Atrial cells Connective tissue

1 mm

40 30

30

35

2520

15

105

0

35

40 4550

55

60

65

70

SEP

CT

CT

EpiCompact

IVC

RA

SVCA

B

Nodal cells

Endo

Figure 1. Diagram showing the major tissue types and anatomy ofthe rabbit SA node when viewed from the endocardial surface (A)and in cross-section (B). The various tissue types are color-coded asindicated. The dashed yellow line shows the extent of the nodal tissueunderlying the atrial tissue. The dark dotted lines show isochronesat the times indicated (in ms) for the propagation of an impulseaway from the leading pacemaker site.

Abbreviations: CT, crista terminalis; Epi, epicardium. Endo, endo-cardium; IVC inferior vena cava; RA, right atrial appendage; SA, sino-atrial (node); SEP, interatrial septum; SVC, superior vena cava. Redrawn from reference 3: Bleeker WK, Mackaay AJ, Masson-Pevet M, Bouman LN, Becker AE. Functional and morphologicalorganization of the rabbit sinus node. Circ Res. 1980;46:11-22.Copyright © 1980, Lippincott Williams & Wilkins.

CELLULAR ELECTROPHYSIOLOGY OF SINGLE NODAL CELLS

Regional differences within the node

The vast majority of cells within the node show theslow diastolic pacemaker depolarization phase that isthe defining characteristic of the SA nodal action po-tential (Figure 3A) and provides the fundamental req-uisite "clock function." However, the exact shape ofthe action potential varies among the differing celltypes within the node reflecting an underlying hetero-geneity of ion channel expression across the node.2,8

The small cells, presumed to be from the center of thenode, have lower resting membrane potentials and aslower diastolic depolarization phase than the largerperipheral cells.8 The smaller cells also have a slowaction potential upstroke, reflecting a low expressionof Na channels and a depolarization phase dominatedby Ca inward current. In moving away from the centerof the node towards the periphery, the expression ofNa channels increases and with this comes a faster,taller action potential.8 Isolated peripheral nodal cellsalso show an increase in their spontaneous beatingrate (above that seen in situ) and an increased rate of diastolic depolarization—most likely as a conse-quence of an increase in the pacemaker current If.9,10



8

Large cell—peripheral?

0 mV

–50 mV

Faster pacemaker potential – increased If

Shorter action potential

Faster upstroke – (increased INa) – higher peak potential

More negative minimumdiastolic potential

500 ms

B

Small cell—central?

0 mV

–50 mV

Slower pacemaker depolarization and morepositive takeoff potential

Longer action potential

Slower upstroke (ICa)– lower peak potential

Less negative minimumdiastolic potential

A

Figure 2. Photomicrographs of the fourdifferent cell types isolated from the rabbitsinoatrial (SA) node. Cells are stainedwith hematoxylin and eosin.

Reproduced from reference 7:Verheijck EE, Wessels A, van Ginneken AC,et al. Distribution of atrial and nodal cellswithin the rabbit sinoatrial node: modelsof sinoatrial transition. Circulation.1998;97:1623-1631. Copyright © 1998,Lippincott Williams & Wilkins.

Figure 3. Spontaneous action potentials recorded from two cells isolatedfrom rabbit sinoatrial (SA) node. A: recording from a small cell (22pF)

assumed to be from the center of the node. B: recording from a large cell(57.5pF) assumed to be from the periphery of the node.

Reproduced from reference 8: Honjo H, Boyett MR, Kodama I,Toyama J. Correlation between electrical activity and the size of rabbit

sino-atrial node cells. J Physiol. 1996;463:795-808. Copyright ©1996, Cambridge University Press.

SA nodal cells Atrial cell

30 µm

Spindle cell

Center?

Elongated spindle cellPeriphery?

Spider cell

?

This increase in firing rate of the peripheral tissue isprobably a feature of isolated cells as, in the intactheart, the electrotonic coupling of these cells to thesurrounding atrial tissue is likely to counteract thiseffect.2

The heterogeneous distribution of ion channel expres-sion in the various regions of the node allows the pri-mary pacemaker site to "wander" according to prevailingconditions.2 Activation or inhibition of a particularchannel thus does not inhibit the node altogether, butsimply allows the primary pacemaker site to shift to aregion of the node where these channels play a moreminor role.2 This spatial heterogeneity is thus a keysafety feature of the node making it very hard to stop.

Multiple currents make the node both hard to stop and

exquisitely regulatable

Not only does the spatial heterogeneity of ion channelexpression provide a fail-safe pacemaker, but withinindividual cells the multiple ionic currents underlyingpacemaker activity provide layers of redundancy. Figure 4shows a computer simulation (Oxsoft Heart v 4.0) ofthe principal ion currents underlying the SA node ac-tion potential. For comparison, these currents have allbeen plotted on the same vertical scale. At least 10ionic currents have now been identified as contributingto the SA node action potential.11,12 However, Irisawaet al (1993) have pointed out only two currents are re-quired to produce rhythmic activity in nodal cells—atime-independent outward current and the Ca inwardcurrent (ICa).13 Thus, the multiple ionic currents withinnodal cells provide levels of redundancy that again makethe node hard to stop—a very useful safety feature.

Figure 4 also shows another key feature of the node:that is, currents known to exert a substantial effect onrate (such as the pacemaker current If) may only bequite small under physiological conditions. While therole of If in pacemaker function has been extensivelydebated and investigated,14,15 it is clear that the selec-tive blockade of this small current can undoubtedlymodulate rate in vivo (see below and Borer et al16).Thus, not only do the multiple ion currents of the SA

node provide a fail-safe mechanism they also providefor exquisite regulation, as small currents (or smallchanges in large currents) can fundamentally influenceSA node rate.

How can small currents have such a big effect on heart rate?

In ventricular cells, the resting membrane potential isdetermined principally by the high permeability of themembrane to potassium ions and the intra- and extra-cellular potassium concentrations. Thus, in ventricularmyocytes, the resting membrane potential (ie, wherenet current flow is zero) is typically around –85 mV.The relationship between current flow and voltage isdescribed by Ohm’s Law (Voltage = Current � Resist-ance; or V=IR). Figure 5A (next page) shows this rela-



9

0

–120

–80

–40

200 ms

Na/Ca exchangecurrent (pA)

Pacemakercurrent If (pA)

Background Na current (pA)

Delayed rectifier IK (pA)

L-type Ca current (pA)

Voltage (mV)

160

–120

80

120

–160

–80

0

–40

0

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40

–40

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–40

Figure 4. Principal ionic currents responsible for pacemaker activityin the sinoatrial node. These currents were calculated using the

Oxsoft Heart model (v4.0). To allow comparison, all currents areplotted using the same vertical scale and hence the peak of the

L-type calcium current is off-scale at around –470 pA. The T-typeCa current is small in this model and is not shown. In addition, the

current generated by the electrogenic Na/K pump is also not shown.

tionship for the resting membrane of a ventricularmyocyte, and this steady-state current through potas-sium channels is carried by the inward rectifier—IK1.This current-voltage relationship crosses the voltageaxis at the resting membrane potential (ie, around–85 mV) and, because the membrane is very permeableto potassium at these voltages, the slope of this rela-tionship is steep (ie, conductance is high). Thus, ataround –85 mV, where the "resistance" of the membraneis low, a small current has only a small effect on mem-brane voltage (Figure 5A inset). This makes the restingpotential of a ventricular cell inherently stable andprotects the cell against inappropriate excitability andarrhythmias—a useful feature for ventricular cells.Contrast this with the situation in a SA node cell (Fig-ure 5B). The input impedance (resistance) of the SAnode cell is ≈30 times that of a ventricular myocyte17,18

(ie, the slope of the I-V relationship is much shallower).SA node cells lack the inward rectifier current (IK1)that provides the high K permeability to resting ven-tricular cells. A small change in current in an SA nodecell can thus result in a large change in membranepotential (Figure 5B inset). Thus, the membrane poten-tial of SA node cells is, by design, inherently unstableand very small changes in current can profoundly in-fluence the shape of the action potential. The high-input impedance of SA node cells thus means that the

intrinsic rate of firing of the node is exquisitely regu-latable through small modulations of the ion currentsunderlying the pacemaker depolarization.

THE "PACEMAKER CURRENT" IF

Characteristics

In 1979, Brown and colleagues in Oxford identified aninward current in SA node preparations that had theunusual property of being activated on hyperpolariza-tion of the cell membrane.19 At this time, a hyperpo-larization-activated inward current was so unusual itwas termed the "funny" current—If . Since then, asimilar current carried, as it transpires, by the samefamily of channels, has been identified in neuronaland retina cells and has been termed the hyperpolar-ization-activated current Ih (see Pape20 for review).

Figure 6 shows the principal property of If —that is, itis activated by hyperpolarizations negative to –50 mV.If can be carried by a mixture of Na and K ions (al-though Na is the major carrier in physiologic settings)and has all the features necessary to be a primarypacemaker current in the heart.21,22 For example, If : (i) is activated on hyperpolarization from a threshold ofabout –50 mV (and is fully activated around –110 mV)

10



Ventricular myocyte

–120 –80 –40 40

Outward current

Membrane potential (mV)

Smallcurrent

Smalleffect on Em

Inward current

High restingpermeability

to K sets membrane

potential near –85 mV

A

Sinoatrial node cellB

–50 –25 25 50

–80–120 –40

Outward current

Membrane potential (mV)

Inward current

Smallcurrent

Big effect on Em

Figure 5. Illustration of the differences incurrent-voltage (I-V) relationships for thesteady-state background current in ventricularmyocytes and sinoatrial (SA) nodal cells. A: representation of the steady-state I-V rela-tionship for IK1 in ventricular cells showing it intersecting the voltage axis at the restingmembrane potential. The K+ conductance ofthe resting membrane is high (ie, the slope ofthe I-V relationship is steep) such that a smallcurrent exerts only a small effect on membranepotential (see inset). B: shows the lack of IK1

in the SA node cell gives a shallow steady-state I-V relationship (ie, low conductance,high impedance) and hence a small currentcan induce a large change in membrane voltage (see inset).

The data in B are redrawn from refer-ence 17: Noma A, Nakayama T, Kurachi Y,Irisawa H. Resting K conductances in pace-maker and non-pacemaker heart cells of the rabbit. Jpn J Physiol. 1984;34:245-254.Copyright © 1984, Center for AcademicPublications Japan.

and hence contributes to diastolic "pacemaker" depo-larization; (ii) is increased by β-receptor stimulation;and (iii) is inhibited by acetylcholine (ACh).21

Role of If in the control of heart rate

While it is clear that If may influence pacemaker func-tion, the extent to which it is important in the controlof heart rate has been hotly debated.14,15,23,24 WhileDiFrancesco and colleagues14,25 have argued that If isexclusively responsible for pacemaker activity, othershave suggested that it plays only a minor role.15,23,24,26

The roots of some of this controversy are illustrated inFigure 6A. The diastolic depolarization phase of theSA node action potential shows a maximum diastolicpotential of –60 to –65 mV, which depolarizes graduallyto about –55 mV over about 200 ms. From Figure 6B,however, it is clear that If is both slow to activate and

small at these voltages. Thus, 100 to 200 ms into thevoltage-clamp steps shown in Figure 6B, at voltagesbetween –65 and –55 mV, If will only reach about 40 pAat most. These observations, and others, have lead tothe suggestion that If does not play a major role incardiac automaticity, but simply is there to prevent ex-cessive hyperpolarization.2,15,23,24,26

Much of the debate about If and its importance, or lackthereof, in pacemaking relates to the specific detailsand conditions under which in vitro experiments areperformed.14,15 A simpler and pragmatic answer to thequestion, “Does If contribute to pacemaker function inman?” is provided by the clinical studies of agents re-ported to be specific and selective for If inhibition. Forexample, ivabradine (0.3-3 µM) is a potent inhibitorof If 27 and, at these concentrations, has been shown toreduce heart rate by 10 to 15 bpm in clinical studies.16

Since ivabradine has been shown to be selective for If

at these concentrations,27 this would suggest that If

does indeed contribute to the control of heart rate invivo. What is clear from this debate is that while If

certainly contributes to pacemaker function, it is notthe sole determinant of rhythmic activity. This againshows that there are levels of redundancy within theSA node that provide a fail-safe feature such that thatcardiac rhythm can be both initiated and regulated inthe event of the failure of any given mechanism.

Regulation of If

The firing rate of the SA node is exquisitely modulatedby innervation from the autonomic nervous system.Basal heart rate is under the influence of a maintainedvagal tone and sympathetic stimulation can dramatical-ly increase heart rate. In isolated SA node cells, β-re-ceptor stimulation increases, and ACh slows, the rateof SA node cell diastolic depolarization (Figure 7A,next page). The original description of If by Brown etal in 1979 showed that this current is substantially in-creased by β-receptor stimulation.19 Figure 7B showsa series of steady-state activation curves for If .28 Thesecurves describe the fraction of channels activated at a given potential and the control curve shows that at–60 mV only ≈23% of available channels are activated.However, β-receptor stimulation shifts this activationcurve to the right such that at –60 mV there is an 87%increase in available channels. Conversely, ACh shiftsthe activation curve to the left, reducing the availablechannels at –60 mV by 70%.

These shifts in the activation curve for If are mediat-ed by changes in intracellular concentration of cAMP.



11

500 pA

mV

500 ms

500 ms

B

A

–45 mV–55 mV

–65 mV–75 mV

–45

–55

–65

–75

–70

0

Figure 6. Spontaneous action potentials recorded from an isolated SAnodal cell (A) and the hyperpolarisation-activated ( If) current recordedin response to voltage-clamp steps (B). The dotted lines in A indicate thevoltages of the clamp-steps shown in B. This illustrates that, in this case,the diastolic depolarization phase of the action potential goes from around–60 mV to around –50 mV in about 150 ms. Note: the slow activation kinetics of the currents shown in panel B mean that, at these voltages,the activation of If is relatively small after 150 ms.

Redrawn from reference 22: Baruscotti M, DiFrancesco D. Pacemakerchannels. Ann N Y Acad Sci. 2004;1015:111-121. Copyright © 2004,New York Academy of Sciences.

β-Receptor stimulation, through its activation of adeny-lyl cyclase, elevates cAMP, which then binds directlyto the cytoplasmic tail of the If channel, shifting itsactivation curve to the right. Conversely, ACh, via mus-carinic receptors, inhibits adenylyl cyclase, decreasescAMP, and shifts the I f activation curve to the left.DiFrancesco and colleagues have argued that this isthe explanation for the negative chronotropic effectsof ACh in contrast to the established textbook explana-tion—that is, ACh activates an ACh-dependent K cur-rent (IK,ACh).29 In support of this, these authors haveshown that low concentrations of ACh (0.01-0.03 µM)inhibit If without affecting IK,ACh, and an increase inIK,ACh requires 20 times the concentrations requiredto inhibit If .29

In addition to the modulation of If by autonomic neu-rotransmitters, a number of other physiologically-rele-vant agents have been shown to modulate this current.Activators of If include vasoactive intestinal peptide(VIP),30 thyroid hormone (T3),31 and nitric oxide,32 whileIf is inhibited by neuropeptide Y (NPY) and adenosine.33

Molecular identity and tissue distribution of If channels

The channel responsible for the cardiac If current is nowknown to be a member of a family of channels termedthe hyperpolarization-activated cyclic nucleotide-gatedcation (HCN) channels (for review see reference 22).Four HCN genes have been identified in mammaliantissues, termed HCN1-4. RNA messages for all 4 HCNisoforms have been found in heart,34 but in the SAnode HCN4 is the dominant isoform in most species,accounting for ≈80% of the messages.35-37 In mouse,HCN2 makes up the remainder with only very low lev-els of HCN1.37 This is not the case in rabbit where the remaining 20% is mostly HCN1.36 HCN1 is highly expressed in retinal photoreceptors37,38 and in thebrain.39,40 HCNs 2 and 3 are also expressed in brain.40,41

Within the SA node the expression of HCN channels isnot uniform. Cells from the center of the node showlittle If current, while towards the periphery If is larg-er,9,10 and this correlates with a heterogeneous expres-sion of HCN4 channels.42

Studies in knockout mice have shown that the homozy-gote deletion of the gene encoding HCN4 is embryolog-ically lethal.43 However, hearts and cardiomyocytescould still be isolated from these embryos and theyshowed If reduced by 80% and heart rate by about 40%.Importantly, the HCN4-deficient hearts still contractedregularly without arrhythmias, showing that, as sug-gested above, while If clearly contributes to pacemakerfunction, it is not the sole determinant of rhythmicity.Interestingly, the contraction rate in HCN4-deficienthearts was unaffected by raising cAMP, suggesting thatthis channel not only contributes significantly to basalheart rate, but also mediates the chronotropic re-sponse to adrenergic stimulation.43



12

100%

Control

ACh(3 nM)

Iso(10 nM)

Control

ACh(3 nM)Iso

(10 nM)

23%

0%

mV

100 ms

B

A

20 mV

Fractionof channelsactivated

87%increase

70%decrease

–100 –50 0

Figure 7. Effect of �-receptor and muscarinic-receptor stimulation on: (A)spontaneous action potentials recorded from an isolated sinoatrial (SA) nodalcell; and (B) the steady-state activation curve for If . Isoprenaline (Iso) accel-erates, and acetylcholine (ACh) slows, the spontaneous rate of an isolated SAnode cell by altering the rate of diastolic depolarization. The shaded area inboth panels indicates the diastolic voltage range from –45 to –70 mV. Panel Bshows that at –60 mV only 23% of the available channels are activated.However, the fraction of channels available increases by 87% in isoprenaline(10 nM) or decreases by 70% in response to ACh (3 nM).

Panel A is redrawn from reference 21: DiFrancesco D. Pacemaker mecha-nisms in cardiac tissue. Annu Rev Physiol. 1993;55:455-472. Copyright ©1993, Annual Reviews. Panel B is redrawn from reference 28: Accili EA, Robinson RB, DiFrancesco D.Properties and modulation of If in newborn versus adult cardiac SA node. Am J Physiol. 1997;272(3 pt 2):H1549-1552. Copyright © 1997, AmericanPhysiological Society.

Consequences of If block

An elevated resting heart rate has been shown to cor-relate strongly with increased mortality in angina,44

heart failure,45 and even cancer.46 While the literaturesuggests that heart rate represents an independentrisk factor,46,47 it is possible that it is an epiphenomeno-logical indicator of an underlying increase in sympa-thetic tone. In recent years the pharmaceutical industryhas searched for pure bradycardic agents that canlower heart rate without the negative inotropic conse-quences of β-blockade or Ca antagonism.48 The list ofsuch specific bradycardic agents (SBAs) now includesalinidine, zatebradine, and ivabradine. Figure 8A showsthat ivabradine (0.3 µM) slows the rate of diastolicdepolarization in an SA node cell, and hence slows thefiring rate of this cell (in this case by approximately

18%), without changing the shape of the subsequentaction potential.22 The inhibitory action of ivabradineon If is shown in Figure 8B where a higher concentra-tion (3 µM) reduces If by ≈78%. Ivabradine blocks thechannel when it is in its open state and hence its blockis use-dependent—that is, in isolated tissues itsability to block the channel increases as the beatingrate increases.27 While such use-dependence soundsan attractive feature (ie, the drug should exert a largereffect when heart rate is high) evidence from Borer etal16 (2003) suggests that in man the negative chrono-tropic effect of ivabradine in absolute terms is com-parable at rest and during peak exercise.

Figure 8C shows a computer simulation (Cellular OpenResource; COR - Oxford University)49 of the effects ofthe complete blockade of If on the SA node actionpotential. This model predicts that, under steady stateconditions, complete blockade of I f will reduce SAnode rate by approximately 20% to 30% in an isolatedcell. This demonstrates the fail-safe feature of SAnode cells discussed earlier—that the intrinsic pace-maker activity of the node is not dependent on a sin-gle ionic current and hence intrinsic pacemaker activ-ity at the level of a single cell or, when integratedacross the entire node, is hard to stop.

Figure 9A (next page) shows the dose-response rela-tionship for ivabradine in isolated SA node cells27 witha half-maximal inhibitory concentration of 2.2 µM.Figure 9B shows a dose-titration study in patients wherethe dose of ivabradine has been increased stepwisefrom 5 to 20 mg bid. In Figure 9B, it is interesting tonote that the major bradycardic effect is seen on goingfrom control to 10 mg (bid). Further increases in doseabove 10 mg result in only a small further drop in heartrate, indicating there appears to be a "plateau effect"such that the maximal drop in heart rate seen in thisstudy plateaus at about 30%. This is in accordance withthe in vitro and simulation data shown in Figure 8,suggesting that even complete block of If will not cause



13

Control Ivabradine(0.3 µM)

Control

Ivabradine(0.3 µM)

Control Completeblock of If

100 ms

B

C

A

500 ms

2 s

20 mV

20 mV

200 pA

–35 mV+5 mV

–70 mV

Figure 8. Effects of inhibition of If on spontaneous action potentials froman SA node cell (A), and current recorded in a voltage-clamped sinoatrial(SA) node cell (B), and a computer model of the SA node action potential (C).A: Ivabradine (0.3 �M) slows the spontaneous rate of an isolated SA nodecell by slowing the diastolic depolarization phase without affecting theshape of the subsequent action potential. B: Ivabradine (3 �M) blocks If

in a voltage-clamped isolated SA node cell. C: Complete block of If in acomputer-simulated model of the SA node action potential using the CellularOpen Resource program developed by Noble and colleagues49 slows, butdoes not abolish, repetitive activity.

Redrawn from reference 22: Baruscotti M, DiFrancesco D. Pacemakerchannels. Ann N Y Acad Sci. 2004;1015:111-121. Copyright © 2004,New York Academy of Sciences.

severe bradycardia or sinus arrest. Thus, assumingivabradine is indeed selective for the If channel, then,at least in terms of cardiotoxicity, this agent is likely tobe safe and of potential therapeutic benefit in patholo-gies where lowering the heart rate is desirable.

CAN "FAIL-SAFE" GO TOO FAR? THE PLUSES AND MINUSES OF

INTERACTIVE BACKUP SYSTEMS

As detailed above, one of the positive aspects of apacemaker whose function is supported by multipleion currents is that in the event of malfunction of partof the system, other limbs may come into play. Forexample, excess hyperpolarizing action of outward Kcurrents may be counteracted by the activation of theinward If pacemaker current. The rapid rates that maybe achieved with excess increases in net inward currentor decreases in repolarizing current may be attenuatedby enhanced vagal tone to decrease I f and increaseI K,Ach. The latter current provides yet another meanswhereby hyperpolarization and a decrease in diastolicdepolarization and pacemaker rate may be achieved.

A further fail-safe mechanism is provided by the dis-persion of pacemaker cells within the SA node. Thedissemination of anatomically and electrophysiological-ly defined pacemaker tissue within the region of theSA node is such that more than one site can functionas the pacemaker, with the most rapid site of impulseinitiation overdrive-suppressing the slower sites. Auto-nomic tone and other less-well defined interventionsalso influence both site and rate of cardiac pacemaking.

A problem that arises is in the setting of SA nodal dys-function, where bradycardias and tachycardias mayoccur often in seemingly haphazard juxtaposition, al-though the initiation of tachycardia after a period ofbradycardia has been well defined. Treatment is oftendifficult and may involve the use of SA nodal ablationand device therapy. One might question whether thissyndrome, or family of syndromes, arises from a mal-function in the primary pacemaker current, If , or inone of the other currents that contribute to the pace-maker potential. Alternatively, does it come about as aresult of structural abnormalities in the nodal region,such as excess uncoupling of pacemaker cells from oneanother and the surrounding tissues? These are issuesfor which there are currently no answers and whichmust be solved if we are to contend with this impor-tant cardiac rhythm disturbance.

CONCLUSION

In summary, the mammalian SA node is a complexheterogeneous mixture of nodal cells, atrial tissue, andconnective tissue. The nodal cells themselves are bothmorphologically and electrophysiologically heteroge-neous and it is this macro- and micro-diversity that iskey to the functioning of the node. The heterogeneousion channel expression in different regions of the nodeand the multiple ion channels within a single cell thatcontribute to pacemaker activity make the node fail-safe and very hard to stop. The multiple currents con-tributing to the pacemaker depolarization, and the high



14

100

I f in

hib

itio

n (

%)

10–8 10–7 10–6 10–5 10–4

IC50 =2.2�10–6 M

Ivabradine dose (mg bid)

Concentration of ivabradine (M)

50

0

75

HR

(b

pm

)

0 D0 D7 D14 D21

10 15 20

45

30

60

B

AFigure 9. Dose-dependent effects of ivabradine on If (A) and heart rate (HR)(B). A: Dose-response curve for steady-state block of If measured in a rabbitsinoatrial node cell paced at 6 Hz with a 1.8 s voltage-clamp step from –30 mV to –100 mV. B: Effects of ivabradine on heart rate from a dose-titrationstudy in which ivabradine concentration was incrementally increased every 7 days from control (0) to 20 mg (bid).

Panel A is redrawn from reference 27: Bois P, Bescond J, Renaudon B,Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents ofrabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. Copyright© 1996, Nature Publishing Group.

Panel B is based on reference 50: European Public Assessment Report.London, UK: EMEA; 2005:20.

input-impedance of the nodal cells, mean that notonly is the node hard to stop, but it is also exquisitelyregulatable. That is, small currents can exert signifi-cant effects on heart rate. One such small current thatappears to play a crucial regulatory role is the hyper-polarization-activated cyclic nucleotide gated cationchannel that conducts the "funny" current If . Prevailingevidence suggest that it is this current that is the targetfor both the adrenergic and cholinergic modulation ofheart rate. If is also the target for a new class of spe-cific bradycardic agents such as ivabradine that havethe potential to safely and selectively lower heart ratewithout the inotropic consequences of other rate-slow-ing agents such as the β-blockers or Ca antagonists.The fail-safe nature of the node and the specificity ofivabradine suggest that this agent should be a safe andeffective way of lowering heart rate without the risk ofprofound bradycardia or sinus arrest. Results of theBEAUTIfUL trial (MorBidity-mortality EvAlUaTion of theIf inhibitor ivabradine in patients with coronary dis-ease and left ventricULar dysfunction), which concludesin December 2007, should shed more light on theclinical benefits expected from this promising agent.

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Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sino-atrial node.

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Electrophysiological study of the two main pacemaker mechanismsin the rabbit sinus node.


11. Shattock MJ.

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12. Boyett MR, Harrison SM, Janvier NC, McMorn SO,Owen JM, Shui Z.

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13. Irisawa H, Brown HF, Giles W.

Cardiac pacemaking in the sinoatrial node.

Physiol Revs. 1993;73:197-227.

14. DiFrancesco D.

The pacemaker current If plays an important role in regulating SAnode pacemaker activity.


15. Vassalle M.

The pacemaker current If does not play an important role in regulating SA node pacemaker activity.


16. Borer JS, Fox K, Jaillon P, Lerebours G.

Antianginal and anti-ischemic effects of ivabradine, an If inhibitor,in stable angina: a randomized, double-blind, multicentered,placebo-controlled trial.

Circulation. 2003;107:817-823.

17. Noma A, Nakayama T, Kurachi Y, Irisawa H.

Resting K conductances in pacemaker and non-pacemaker heartcells of the rabbit.

Jpn J Physiol. 1984;34:245-254.



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18. Irisawa H, Brown HF, Giles W.

Cardiac pacemaking in the sinoatrial node.

Physiol Rev. 1993;73:197-227.

19. Brown HF, DiFrancesco D, Noble SJ.

How does adrenaline accelerate the heart?

Nature. 1979;280:235-236.

20. Pape HC.

Queer current and pacemaker: the hyperpolarization-activatedcation current in neurons.

Annu Rev Physiol. 1996;58:299-327.

21. DiFrancesco D.

Pacemaker mechanisms in cardiac tissue.


22. Baruscotti M, DiFrancesco D.

Pacemaker channels.

Ann N Y Acad Sci. 2004;1015:111-121.

23. Noma A, Morad M, Irisawa H.

Does the “pacemaker current” generate the diastolic depolarizationin the rabbit SA node cells?

Pflugers Archives. 1983;397:190-194.

24. Boyett MR, Kodama I, Honjo H, Arai A, Suzuki R,Toyama J.

Ionic basis of the chronotropic effect of acetylcholine on the rabbitsinoatrial node.


25. DiFrancesco D.

The onset and autonomic regulation of cardiac pacemaker activity:relevance of the f current.


26. Denyer JC, Brown HF.

Pacemaking in isolated rabbit sino-atrial node cells during Cs+

block of the hyperpolarization-activated current If .

J Physiol. 1990;429:401-409.

27. Bois P, Bescond J, Renaudon B, Lenfant J.

Mode of action of bradycardic agent, S 16257, on ionic currents ofrabbit sinoatrial node cells.

Br J Pharmacol. 1996;118:1051-1057.

28. Accili EA, Robinson RB, DiFrancesco D.

Properties and modulation of If in newborn versus adult cardiacSA node.

Am J Physiol. 1997;272(3 pt 2):H1549-1552.

29. DiFrancesco D, Ducouret P, Robinson RB.

Muscarinic modulation of cardiac rate at low acetylcholine con-centrations.

Science. 1989;243:669-671.

30. Chang F, Yu H, Cohen IS.

Actions of vasoactive intestinal peptide and neuropeptide Y on thepacemaker current in canine Purkinje fibers.

Circ Res. 1994;74:157-162.

31. Renaudon B, Lenfant J, Decressac S, Bois P.

Thyroid hormone increases the conductance density of f-channelsin rabbit sino-atrial node cells.

Receptors Channels. 2000;7:1-8.

32. Musialek P, Lei M, Brown HF, Paterson DJ, Casadei B.

Nitric oxide can increase heart rate by stimulating the hyperpolar-ization-activated inward current, If .

Circ Res. 1997;81:60-68.

33. Zaza A, Rocchetti M, DiFrancesco D.

Modulation of the hyperpolarization-activated current If by adeno-sine in rabbit sinoatrial myocytes.

Circulation. 1996;94:734-741.

34. Stieber J, Hofmann F, Ludwig A.

Pacemaker channels and sinus node arrhythmia.

Trends Cardiovasc Med. 2004;14:23-28.

35. Ishii TM, Takano M, Xie LH, Noma A, Ohmori H.

Molecular characterization of the hyperpolarization-activatedcation channel in rabbit heart sinoatrial node.

J Biol Chem. 1999;274:12835-12839.

36. Shi W, Wymore R, Yu H, et al.

Distribution and prevalence of hyperpolarization-activated cationchannel (HCN) mRNA expression in cardiac tissues.

Circ Res. 1999;85:e1-e6.

37. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F,Ludwig A.

Cellular expression and functional characterization of four hyper-polarization-activated pacemaker channels in cardiac and neuronaltissues.

Eur J Biochem. 2001;268:1646-1652.

38. Demontis GC, Moroni A, Gravante B, et al.

Functional characterisation and subcellular localisation of HCN1channels in rabbit retinal rod photoreceptors.

J Physiol. 2002;542(pt 1):89-97.

39. Santoro B, Chen S, Luthi A, et al.

Molecular and functional heterogeneity of hyperpolarization-acti-vated pacemaker channels in the mouse CNS.

J Neurosci. 2000;20:5264-5275.

40. Notomi T, Shigemoto R.

Immunohistochemical localization of Ih channel subunits, HCN1-4,in the rat brain.

J Comp Neurol. 2004;471:241-276.



16

41. Moosmang S, Biel M, Hofmann F, Ludwig A.

Differential distribution of four hyperpolarization-activated cationchannels in mouse brain.

Biol Chem. 1999;380:975-980.

42. Efimov IR, Nikolski VP, Rothenberg F, et al.

Structure-function relationship in the AV junction.

Anat Rec A Discov Mol Cell Evol Biol. 2004;280:952-965.

43. Stieber J, Herrmann S, Feil S, et al.

The hyperpolarization-activated channel HCN4 is required for thegeneration of pacemaker action potentials in the embryonic heart.

Proc Natl Acad Sci U S A. 2003;100:15235-15240.

44. Diaz A, Bourassa MG, Guertin MC, Tardif JC.

Long-term prognostic value of resting heart rate in patients withsuspected or proven coronary artery disease.

Eur Heart J. 2005;26:967-974.

45. Tavazzi L.

Heart rate as a therapeutic target in heart failure?

Eur Heart J. 2003;5(suppl G):G15-G18.

46. Benetos A, Thomas F, Safar ME, Bean KE, Guize L.

Should diastolic and systolic blood pressure be considered for cardiovascular risk evaluation: a study in middle-aged men andwomen.

J Am Coll Cardiol. 2001;37:163-168.

47. Gillman MW, Kannel WB, Belanger A, D'Agostino RB.

Influence of heart rate on mortality among persons with hypertension:the Framingham Study.

Am Heart J. 1993;125:1148-1154.

48. Borer JS.

Drug Insights: If inhibitors as specific heart-rate reducing agents.

Nat Clin Pract Cardiovasc Med. 2004;1:103-109.

49. Garny A, Kohl P, Noble D.

Cellular Open Resource (COR): a public CellML based environ-ment for modelling biological function.

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50. European Public Assessment Report.

London, UK: EMEA; 2005:20.



17

oronary artery disease(CAD) is characterized byobstructions to myocardialblood flow that limit maxi-

mal oxygen delivery to the myo-cardium. In settings of heighteneddemand for flow, as with physicalexertion or emotional stress, theflow limitation can result in myo-cardial ischemia, a pathophysiolog-ical condition in which myocardialoxygen demand exceeds availablesupply. This condition is often ac-companied by angina pectoris, astereotyped chest discomfort thatdevelops reproducibly when the in-citing stress is incurred and is typi-cally relieved within ≤20 minutes ofstress cessation, and is occasionallyassociated with symptoms such asdyspnea and lightheadedness. Angi-na is the most common clinicalmanifestation of CAD. Throughoutthe world, angina is a major causeof debility, particularly among menabove 55 years and women above65 years. Indeed, it is estimatedthat, in Europe and the UnitedStates, 30 000 to 40 000 persons permillion suffer from angina.1-3 Theassociation between exertional chestdiscomfort and CAD, and the asso-ciation between CAD and “prema-ture” death, are both relatively wellrecognized among nonphysicians.Consequently, angina is generallyfrightening for the patient. The com-bination of discomfort and fear as-sociated with angina results in lossof productivity at the workplace andlimitation of the capacity for leisureactivity among afflicted individuals.Therefore, prevention of angina is

a legitimate therapeutic objective,despite the fact that most patientswith angina are at relatively low im-minent risk of death or myocardialinfarction from their underlyingCAD.1,4

Control of angina can be achievedeither by masking the symptomwith analgesia or by eradicating is-chemia, the underlying cause. Theformer strategy may allow continu-ation of the inciting stress withoutthe warning provided by the symp-tom, potentially leading to severeand irreversible myocardial damage.Thus, angina prevention can beachieved with acceptable safety onlyby preventing ischemia, a conceptwell recognized by governmentaldrug regulatory authorities, whichrequire relief of ischemia as well asangina by therapeutics (drugs ordevices) approved for marketing.5

However, angina is not the only clin-ical sequel of coronary occlusion. If both sufficiently abrupt and suf-ficiently severe, occlusion can leadto myocardial infarction, arrhythmia,and sudden death. If myocardialinjury during infarction involves anarea of sufficient size, heart failurecan ensue. This can occur acutelyor can develop late after the acuteevent, when abnormal mechanicalloading of the noninfarcted myo-cardium results in dysfunction ofthese areas, adding to the effect ofthe infarcted zone. Development of myocardial infarction and othersequelae of coronary occlusion involves a sudden reduction in flow

Can If inhibition help in angina? Jeffrey S. Borer, MD

Division of Cardiovascular Pathophysiology and The Howart Gilman Institute for Valvular Heart Diseases - Weill Medical College of Cornell University - The New York Presbyterian Hospital Weill Cornell Medical Center - New York, NY - USA

C

Keywords: coronary heart disease; heart rate; If current; ivabradineAddress for correspondence:Jeffrey S. Borer, MD, 47 East 88th Street, New York, NY 10128-1152(e-mail: [email protected])



21

The case for a rate-lowering ap-proach to the prophylaxis of is-chemia, the underlying cause ofangina, was always firmly ground-ed in physiology and therapeutics.What it lacked, until the researcheffort sparked in 1979 by the dis-covery of the If current, the centralsinoatrial determinant of heart rate,was pharmacological embodiment.Ivabradine, approved in 2005 forangina prevention, displays the ef-ficacy and safety profile of a specif-ic and selective If inhibitor thatwas predicted on pharmacologicalfirst principles: noninferiority versusatenolol and amlodipine in times toST-segment depression and limitingangina, with none of the extrane-ous and negative hemodynamic,inotropic or metabolic effects asso-ciated with �-blockade or calciumchannel blockade. First principlesalso predict improved survival,which awaits confirmation in aclinical trial.

Copyright © 2006 LLS SAS. All rights reserved www.dialogues-cvm.org

through an artery that may alreadybe occluded sufficiently to causeangina with effort. Therefore, drugsthat simply reduce ischemia may besufficient to prevent angina, butmay or may not impact significantlyon the risks of infarction, subsequentheart failure, or sudden death. Asnoted later in this article, heart rateslowing may be uniquely suited tomitigate not only angina, but alsothese other sequelae of CAD.

PATHOPHYSIOLOGY OFMYOCARDIAL ISCHEMIA:

THE ROLE OF HEART RATE

Heart rate is a primary and directdeterminant of myocardial oxygendemand. Thus, its modulation is areasonable strategy for angina pre-vention. However, heart rate canmitigate ischemia by enhancing my-ocardial oxygen supply as well asby reducing demand (Figure 1).Heart rate determines the durationof diastole, the portion of the cardiaccycle during which most coronaryflow occurs. As diastolic duration

increases with constant perfusionpressure, coronary flow increases.Moreover, diastolic duration andheart rate are not related linearly:relatively small decreases in heartrate result in proportionally greaterincreases in diastolic duration andflow. Some coronary flow occurs dur-ing systole. However, because of theanatomy and conduction sequenceof the left ventricle, intramyocardialsystolic pressure is particularlyhigh in the subendocardial region,virtually precluding flow through-out all of systole and rendering thesubendocardium particularly vulner-able to ischemia when epicardialcoronary artery obstruction is pres-ent. Thus, decreases in heart rate,increasing diastolic duration, areparticularly advantageous for en-hancing subendocardial flow.

Given the reduction in myocardialoxygen demand and increase insupply associated with heart rateslowing, it is not surprising that thedevelopment of β-blocking agentsfor angina prevention was undertak-

en largely because of the heart rate–slowing capacity of these drugs.Electrical stimulation of the carotidsinus, developed almost 40 yearsago for angina treatment, is basedon the same concept.6 However,both these modalities, as well ascalcium channel–blocking drugswith heart rate–slowing capacity,have additional direct hemodynam-ic and/or negative inotropic effectsthat may also be important in is-chemia prevention and may directlyaffect heart rhythm and heart failuredevelopment, or may have otheradverse consequences. Thus, assess-ment of the therapeutic effects ofisolated heart rate slowing requiresa therapy highly specific for thisaction, with no other potentiallyconfounding actions. Moreover, todefine the role of pure heart rateslowing for ischemic heart disease,it is necessary to determine not onlythe capacity for angina prevention,but also the impact on acute myo-cardial infarction, heart failure, andsudden death.

If INHIBITION AND HEART RATE SLOWING:

EXPERIMENTAL CONSIDERATIONS

A quarter century ago, the If currentwas discovered7 and was recognizedas a central physiological determi-nant of heart rate.8 Thus, inhibitionof this cyclic-nucleotide-gated, volt-age-dependent, mixed sodium-potassium current is a legitimatebasis for ischemia prevention. Morethan a decade elapsed from discov-ery of the current to synthesis of a molecule, ivabradine,9 capable ofachieving sufficient If current inhi-bition to prevent angina by heartrate slowing, while devoid of unac-ceptable adverse effects at antiang-inal doses. Preclinical testing todemonstrate potential benefits andto identify possible risks, followedby clinical testing to demonstrate


Can If inhibition help in angina? - Borer

22

MVO2

Ischemia

HEART RATE

Angina pectoris

DEMAND ( )→

SUPPLY ( )

→

Epicardial coronary artery obstruction

Subendocardial systolic resistance →

→

→

Subendocardial blood flow

Diastolicinterval

→

Total coronaryblood flow

→→ → →

Figure 1. Schematic of the relation of heart rate to the pathophysiology of ischemia and anginapectoris due to coronary artery obstruction.

efficacy and acceptable safety forangina prevention, required morethan another decade. This work cul-minated in 2005 with regulatoryauthority approval of ivabradine bythe European Medicines EvaluationAgency (EMEA) as the first If cur-rent inhibitor marketable for anginaprevention. Preclinical evaluationand early clinical studies suggestthat pure heart rate slowing with thisdrug may be beneficial in preventingother sequelae of coronary occlu-sion as well, and, particularly, thatpure heart rate slowing with ivabra-dine is devoid of negative inotropiceffects.10-13 As yet, however, the ben-efits expected as a result of thesefindings have not been proven byadequate and well-controlled clini-cal trials.

The following section reviews theclinical evidence that pure heartrate slowing as demonstrated withthe If current inhibitor ivabradineis effective in angina prevention.

If INHIBITION AND HEART RATE SLOWING:CLINICAL TRIALS FORANGINA PREVENTION

Controlled clinical trials and asso-ciated studies to evaluate the ben-efit of ivabradine for angina pre-vention have involved almost 5000patients with CAD and chronic sta-ble angina. Trials generally contin-ued active treatment for at least 3 months, ie, long enough to allowemergence of drug effects and toevaluate the likelihood of effect per-sistence during chronic therapy,based on empirical evidence withdrugs indicated for prevention ofangina. No other antianginal hasbeen studied so intensively. The drughas been assessed as monotherapy(ie, compared with placebo in theabsence of any background therapy);it has been compared with placeboon a background of amlodipine, the

calcium channel blocker most com-monly used for angina prevention inEurope; and it has been compareddirectly with amlodipine and withatenolol, the most commonly em-ployed β-blocker in Europe. Thesetrials have resulted in considerableinformation about the efficacy ofivabradine and, together with addi-tional observational and compara-tive experience, have also provideddata about the drug’s safety andbenefit-to-risk relationship.

Ivabradine as monotherapy

Within the regulatory and researchcommunities, the primary eviden-tiary standard for antianginal efficacyis improvement in exercise toler-ance on standard treadmill or bicycleergometric testing.5,14,15 Reductionin exercise-inducible symptomsmust be supplemented by reductionin associated ischemia to demon-strate that treatment is not “mask-ing” angina by an analgesic effect,which might allow patients to exer-cise to severe and potentially lethalischemia without the warning ofsymptoms. Angina frequency in dai-ly living, recorded in diaries, is con-sidered adjunctive evidence, but isnot accepted as primary evidenceof drug efficacy because the intensi-ty of stress inciting angina in dailyliving cannot be determined fromdiary reports. Drug effectivenessneeds to be demonstrated at theend of the prescribed interdose in-terval (“trough”), though the effectalso should be demonstrated at thetime of maximal drug effect (“peak”).

The first large trial to assess pureheart rate slowing with ivabradine,carried out according to the prin-ciples noted above, involved 360patients from multiple centersthroughout several European na-tions.16 Patients had documentedevidence of coronary occlusive dis-ease, ambient angina, and ≥0.1 mV

(ie, ≥1 mm) downsloping or horizon-tal electrocardiographic ST-segmentdepression induced by upright bicy-cle ergometry. These patients wererandomly assigned to either placeboor to ivabradine 2.5 mg orally twicedaily, 5.0 mg twice daily, or 10 mgtwice daily, using a double-blind,parallel design (Figure 2, next page).16

The initial treatment assignmentwas continued for 2 weeks (“doseranging”) after which, during anopen-label extension, all patientswere invited to use ivabradine 10 mgtwice daily. Inclusion in this exten-sion was voluntary and dependedin part on appropriately permissivelocal regulations. After 2 to 3 monthson the open-label regimen, pa-tients were randomized to continueivabradine 10 mg twice daily or tobe withdrawn to placebo, underdouble-blind conditions. After 1 week of double-blind withdrawal,a final exercise tolerance (ETT) assessment was performed.

Of the 360 patients initially included(intention to treat [ITT] population),voluntary withdrawals or protocolviolations affected 103 patients,leaving 257 patients treated accord-ing to protocol. These patients wereincluded in the primary (per proto-col [PP]) analysis. With all doses ofivabradine, time to limiting anginawas nominally greater than withplacebo (Figure 3, page 25).17 Thisdifference reached statistical signif-icance when ivabradine 10 mg twicedaily was compared with placebo.16

In addition, a dose-effect relation-ship was apparent when all doseswere considered, and a between-group comparison was statisticallysignificant (P=0.049). For the ITTpopulation, in which protocol viola-tors were included, ivabradine 10 mgbid also was superior to placebo at trough, but the difference wasminimally outside the statisticallysignificant range, reaching the levelof “statistical trend” (P=0.058).



23

Ivabradine 10 mg bid was adminis-tered open-label to 173 study participants. Compared with prior,blinded, regimens, those who in-creased to 10 mg bid nominally increased time to limiting anginain bicycle ergometry, while nochange was apparent in the group

already receiving 10 mg bid. How-ever, among those who then werewithdrawn to placebo, time to lim-iting angina fell significantly, butremained unchanged in patientsmaintained on ivabradine 10 mgbid (between-group difference:P=0.018).16

Consistent with an anti-ischemic aswell as an antianginal effect, timeto 1-mm ST-segment depression wassignificantly reduced by ivabradine5 mg bid and 10 mg bid; a signifi-cant dose-response relationship wasseen across all doses for this effect.Diary recordings and tabulation of



24

Selection, washout, and run-in phasePlacebo

529 screened

Ivabradine2.5 mg bid

Double-blinded, dose-ranging phase360 randomized

Randomized withdrawal phase157 randomized

400 screened

129 not eligible(101 target disease not proven, 8 unstable CAD, 7 consent withdrawn, 13 other reasons)

40 not included(23 negative ETT at D0, 5 unstable CAD, 3 unstable ETT results, 2 consent withdrawn, 7 other reasons)

90 included87 completed3 withdrawn (1 AE, 1 lack of efficacy, 1 nonmedical)PP n=64

Ivabradine 10 mg bid77 included76 completed1 withdrawn (nonmedical)PP n=59

Placebo80 included79 completed1 withdrawn (AE)PP n=65

Ivabradine5 mg bid

91 included87 completed4 withdrawn (1 AE, 1 lack of efficacy, 1 nonmedical, 1 major protocol deviation)PP n=59

Open-label extension phaseIvabradine 10 mg bid

173 included(46 from 2.5 mg bid, 46 from 5 mg bid, 39 from 10 mg bid, and 42 from placebo group)161 completed12 withdrawn(3 AE, 6 lack of efficacy, 1 nonmedical, 2 major protocol deviation)PP n=120

Ivabradine10 mg bid

88 included85 completed3 withdrawn (2 AE, 1 lack of efficacy)PP n=66

Placebo

91 included90 completed1 withdrawn (AE)PP n=68

Figure 2. Protocol andpatient distribution throughall 4 phases of the first largeplacebo-controlled trial ofivabradine as monotherapyfor angina prevention.

Abbreviations: AE, adverseevent; CAD, coronary arterydisease; ETT, exercise tol-erance test; PP, per-protocolpopulation. Modified from reference16: Borer JS, Fox K, Jaillon P, Lerebours G, forthe European IvabradineInvestigators. Anti-anginaland anti-ischemic effects ofivabradine, an If inhibitor,in stable angina: a ran-domized, double-blinded,multicentered, placebo-controlled trial. Circulation.2003;107:817-823. Copy-right © 2003, LippincottWilliams & Wilkins.

short-acting nitroglycerin use con-firmed the antianginal effect by revealing a significant reduction inangina attack rate and nitroglycerinuse during routine daily living atthe end of the protocol comparedwith pretreatment among patientsreceiving ivabradine. At the conclu-

sion of the randomized withdrawal,ambient angina increased amongthose randomly withdrawn to place-bo, but was unchanged amongthose who continued on ivabradine10 mg twice daily.16

This trial also indicated the relativesafety of ivabradine use during a 3-month treatment interval. Adverseevents were relatively few and gen-erally similar in frequency and distribution compared with place-bo, except for relatively minor visu-al symptoms. Visual symptomswere dose-related, were rarely suffi-ciently bothersome to cause volun-tary withdrawal from the drug, andwere invariably reversible duringtreatment or with drug cessation,

consistent with the absence of irre-versible retinal effects reported inpreclinical studies. Visual side ef-fects occurred in approximately 15%at 10 mg twice daily during the dose-ranging phase and 18% during theopen-label phase. (The visual effectsare presumably due to the similarity

between the “f-channels” that me-diate the If current in the sinoatrialnode and “h-channels” that are pres-ent in the retina.) Since the sinoa-trial node is the target of If-inhibit-ing therapy, patients with diseaseof this structure (eg, “sick sinussyndrome”) were excluded fromivabradine trials and, in the currentstate of our knowledge, should notreceive this drug. With this caveatand exclusion, neither syncope noruntoward hypotension nor heartfailure were associated with ivabra-dine administration in the place-bo-controlled trial of the drug asmonotherapy, nor in the other largeclinical trials described below, norwere complaints of untoward fatiga-bility selectively associated with

heart rate slowing with ivabradine(a problem theoretically associatedwith this pharmacological effect).Note, of course, that ivabradinewould be ineffective in patients inchronic atrial fibrillation, since thedrug does not importantly affectthe atrioventricular node and, there-fore, cannot modulate heart rate inthese patients.

Direct comparisons with approved antianginal drugs

at commonly employed doses

These comparisons were designedto test the “noninferiority” of ivabra-dine versus standard antianginaltherapies. Optimally, noninferioritytrials are constructed to demon-strate that a certain portion of theeffect of an established drug is likelyto be retained by a new agent in set-tings in which placebo cannot beemployed.5,15 The requisite portionretained, conventionally acceptedas at least 50% of the effect of thatof the comparator, is believed toindicate the likelihood both of “clin-ical utility” and of equivalence, with-in an acceptable uncertainty basedon the variability of outcome meas-ures in clinical trials. For this con-cept to be rigorously tested, the effect size of the established activecomparator must be precisely de-fined from earlier placebo-controlledtrials. Unfortunately, such informa-tion is seldom available for antian-ginal drugs; historically, these havebeen studied in relatively small tri-als, resulting in relatively unstablepoint estimates of absolute effect.(Also, of course, the use of historicalplacebo-controlled data assumesthe persistence of the backgroundconditions in place at the time ofthe earlier trials, an assumption thatmay not be correct.) In the absenceof precise historical information, oth-er approaches, fundamentally basedon the consensus of experts in thefield, are employed to define the



25

Sec

ond

s (∆

)

Changes in time to limiting angina:ivabradine (trough) at 2 weeks vs baseline

Placebo 2.5 mg bid

*P<0.05*

P=0.049

5 mg bid 10 mg bid

90

80

70

60

50

40

30

20

10

0

Figure 3. Effect of ivabradine, at trough of drug activity, on time to angina suf-ficient to limit continued bicycle exercise among 257 protocol-compliant patientswith coronary artery disease. Measurements were obtained after 2 weeks of double-blind randomized therapy. A dose-response relation is apparent and the dose of 10 mg bid individually is significantly more effective than placebo.

Modified from reference 17: Borer JS. Heart rate reduction: a therapeutic targetin cardiovascular disease. Advances in Cardiology. 2004;1:1-3. Copyright ©2004, LLS.



difference in outcome between newagent and established comparatorthat can be inferred to indicate thatthe effect of the new agent is greaterthan that of the placebo and notinferior to that of the establishedcomparator. The latter approach wasemployed in defining the “margins”for declaring noninferiority betweenivabradine and atenolol and be-tween ivabradine and amlodipine.

In 1195 patients randomized toivabradine 7.5 mg twice daily oramlodipine 10 mg daily, a 3-monthmulticenter, multinational, double-blind study demonstrated thativabradine was indistinguishablefrom amlodipine in its effects on to-tal exercise duration, time to limit-ing angina, time to angina onset,and time to 1-mm ST-segment de-pression. Formal statistical testingof data from this as yet unpublishedtrial revealed ivabradine to be non-inferior to amlodipine (P<0.0001 forthis conclusion).

In a 4-month double-blind study,939 patients were randomized, first,to ivabradine 5 mg twice daily oratenolol 50 mg daily for 2 weeks;then, doses were uptitrated to iva-bradine 7.5 mg or 10 mg twice dailyor to atenolol 100 mg daily.18 Nostatistically significant differenceswere found when various outcomeswere compared among the testedregimens at each stage, and ivabra-dine’s noninferiority to atenolol wassignificantly established at the dos-es employed (P<0001).18 However,despite the fact that atenolol 100 mgdaily resulted in slightly greaterheart rate reduction than with eitherivabradine 7.5 mg or 10 mg twicedaily, ivabradine was nominally su-perior to atenolol in enhancing timeto angina onset, time to limitingangina, and total exercise durationat all doses, while time to 1-mmST-segment depression was virtual-ly identical among the regimens.18

This finding suggests that pharma-cological effects of β-blockers otherthan heart rate slowing may impactnegatively on the pathophysiologyof angina. This hypothesis remainsto be rigorously tested. Importantly,this trial also demonstrated thatunacceptable fatigability was morecommon with atenolol than withivabradine.

Finally, ivabradine was studied in arandomized, blinded modified dose-response trial comparing ivabradine5 mg twice daily versus ivabradine7.5 mg twice daily in 386 patientsfor 1 year.19 At the end of study, bothdoses were associated with a sub-stantial reduction in resting heartrate compared with pretreatmentmeasures, consistent in magnitudewith that found in earlier studies.Also, compared with the pretreat-ment interval, significant reductionsin angina attack rate were associatedwith each dose. Visual symptoms,previously described, were present,but led to treatment cessation inonly 1% of patients. The QT intervalwas rigorously assessed in this studyand, when corrected for heart rate,was not altered by ivabradine ad-ministration, nor were other ECGabnormalities noted.19

Placebo-controlled therapywith amlodipine background

Among 728 patients receiving am-lodipine 10 mg daily throughoutthe study, ivabradine (5 mg twicedaily or 7.5 mg twice daily) wascompared with placebo during a 3-month interval in a randomized,double-blind multicenter, multina-tional trial. These data are not yetpublished and, therefore, cannotbe presented in detail; preliminaryanalysis revealed a statistically sig-nificant superiority of ivabradineversus placebo for both doses atpeak drug effect, with nominal superiority at trough.20

CONCLUSIONS

A growing body of data indicatesthat angina and the underlying is-chemia can be effectively minimizedusing selective sinoatrial node If

current inhibition to slow heart rate.These data also suggest that, whenthis effect is achieved with ivabra-dine, effective prevention of anginais associated with acceptable safetyand tolerability.

Because of the relatively high preva-lence of angina, the availability ofa new approach to angina preven-tion has important public health im-plications. Currently available drugtherapies with single or multipleagents are often inadequate to pro-vide complete or acceptable anginaprevention. According to one recentstudy, most patients with anginareceive combination antianginaltherapy involving at least two drugs,but, nonetheless, continue to ex-perience approximately two anginaattacks per week.21 A new agent,with pharmacological effects differ-ent from currently available drugs,may enhance the rate of acceptableangina relief. Also, since drugs withdifferent pharmacological profilesare likely to differ in frequency, char-acter, and distribution of adverseeffects, tolerability of treatmentacross large populations is likely tobe enhanced by the availability ofa new drug that may be better ac-cepted by some patients for whomother agents are associated withunacceptable adverse effects. Forexample, β-blockers may increasethe symptoms of peripheral arterialocclusive disease22 (commonly as-sociated with CAD) or obstructivepulmonary diseases23 and can in-crease the risk of hypotension orsymptomatic conduction block inpatients with intrinsic atrioventricu-lar node disease.24 Management of diabetes mellitus25 or hyperlipi-demia26 can be confounded by

26



27

β-blockade. Certain calcium channelblockers27 can precipitate or poten-tiate heart failure or atrioventricularnode dysfunction. Calcium channelblockers (particularly the dihydro-pyridines) also frequently causeunacceptable peripheral edema,while all calcium channel blockersoften are associated with constipa-tion. Long-acting nitrates28 cancause severe headaches or can result in lightheadedness or evensyncope (direct results of what arepresumed to be its beneficial phar-macological effects); intermittentuse of nitrates may result in reboundangina and vasoconstriction. Theseadverse effects are not expectedwith If current inhibition and havenot been associated with ivabradineuse. Moreover, as inferable frompreclinical studies (and as yet un-published experience in patientswith heart failure and with left ven-tricular ejection fraction <40%), If

current inhibition with ivabradinedoes not reduce myocardial ino-tropy29,30 (sometimes a problemwith β-blockers12 and certain calci-um channel blockers27) and doesnot result in potentially lethal “re-bound” effects (reported with abruptcessation of β-blockers22,31). Also,from results of the randomized with-drawal after 2 to 3 months of treat-ment during the placebo-controlledtrial of ivabradine as monotherapy,described above, it can be confident-ly inferred that pharmacologicaltolerance to its therapeutic effectsdoes not occur when ivabradine isadministered chronically. Pharma-cological tolerance was identified asan important problem when long-acting nitrates are employed with-out drug-free intervals.32

Finally, in addition to symptom reduction and consequent qualityof life enhancement that can be expected from ivabradine-mediatedIf current inhibition, it is possiblethat heart rate reduction may im-

prove survival. Though the latter hy-pothesis remains to be tested in alarge clinical trial, clinical observa-tions suggest at least one basis forsuch a benefit. Specifically, heartrate slowing appears to minimizethe likelihood of disruption ofatherosclerotic plaques in the coro-nary arteries,33 the pathophysiologypresumed to underlie most myocar-dial infarctions. The putative mech-anism is reduction in mechanicalperturbation of the plaque causedby foreshortening and twisting oflarge epicardial arteries during sys-tole. Perhaps more importantly,when results of multiple clinicaltrials for survival among patientswith heart failure are considered as a group, drug-induced heart ratechanges have been inversely relatedto survival: survival has improvedin proportion to the extent of heartrate slowing and survival has wors-ened when drugs have been asso-ciated with increases in heart rate.34

Similarly, in trials of β-blockers ad-ministered after myocardial infarc-tion, reduction in mortality has beendirectly proportional to the extentof heart rate slowing.35 In a recentlate follow-up of patients enteredinto the Coronary Artery SurgeryStudy (CASS) registry (and, thus,with angiographically-proven CAD),survival among those whose heartrate at entry was <62 beats perminute was 30% greater than sur-vival of those whose entry heart rateexceeded 83 beats/min36; by Coxmodel analysis, the effect of heartrate was independent of other riskfactors. Other, earlier epidemiolog-ical and actuarial studies involvingmore than 150 000 free-living per-sons without specified diseases alsoreveal a significant relation betweencasually measured heart rate andsurvival.37 The intriguing potentialfor survival enhancement withivabradine in patients with CAD and,indeed, in other settings as well,remains to be explored.

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Anti-anginal and anti-ischemic effects ofivabradine, an If inhibitor, in stable angi-na: a randomized, double-blinded, multi-centered, placebo-controlled trial.

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Heart rate reduction: a therapeutic targetin cardiovascular disease.

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29

30


vabradine is a novel pharma-cological agent developed forthe treatment of stable anginapectoris. It is a specific, dose-

dependent, inhibitor of the sino-atrial pacemaker If current and aselective heart rate–lowering agent,which decreases heart rate at restand during exercise, and which hasno negative inotropic effect and noeffect on atrioventricular conduc-tion.1

POTENTIAL CLINICAL EFFECTS OF If CURRENTMODULATION IN HEART

FAILURE

In patients with chronic stable angi-na pectoris, ivabradine reducesheart rate and the rate-pressureproduct (heart rate� systolic bloodpressure), resulting in a reductionin cardiac workload and myocardialoxygen consumption. However, itsheart rate–lowering effect, by reduc-ing the energy cost of overall myo-cardial contractile activity and pro-longing ventricular diastolic filling,could also be beneficial in patientswith left ventricular dysfunction andheart failure. Mortality trials usingphosphodiesterase inhibitors,hydralazine-nitrate, angiotensin-converting enzyme inhibitors, and β-blockers in heart failure patientshave shown a relationship betweenchanges in resting heart rate andmortality reduction (Figure 1).2 Twostudies in patients with severe heartfailure treated with enalapril3 andamiodarone,4 respectively, showedthat baseline heart rate was an im-

portant determinant of the responseto treatment. In these studies, thebenefit of treatment in terms ofsurvival was restricted to patientswith a raised baseline heart rateand was associated with a signifi-cant heart rate reduction.

Nagatsu et al reported evidencethat the benefit of β-blockade onleft ventricular contractility in ex-perimental heart failure associatedwith elevation in baseline heartrate is mediated by heart rate reduc-tion.5 These authors showed thatchronic administration of atenololin dogs with heart failure inducedby creating severe mitral regurgita-tion resulted in a significant im-provement in left ventricular con-

Can If inhibition help in congestive heart failure? Luigi Tavazzi*, MD, FESC; Alessandro Mugelli †, MD, FESC

*Department of Cardiology - IRCCS Policlinico San Matteo - Pavia - ITALY †Center of Molecular Medicine CIMMBA - Department of Pharmacology - University of Florence - Florence - ITALY

Keywords: heart failure; heart rate; If inhibition;electrophysiology; ventricular myocyte; electro-physiological remodeling; ivabradineAddress for correspondence:Alessandro Mugelli, MD, Professor of Pharmacol-ogy, University of Florence, Center of MolecularMedicine CIMMBA, Department of Pharmacology,Viale G. Pieraccini 6, 50139 Firenze, Italy(e-mail: [email protected])


IIvabradine is a selective inhibitorof the If pacemaker current, and assuch decreases heart rate withoutinducing any negative inotropiceffects. Experimental and clinicalevidence suggests that the beneficialeffects of �-blockers in heart fail-ure are mediated by a reduction inheart rate. Long-term heart ratereduction with ivabradine in a ratmodel of heart failure elicited animprovement in left ventricularfunction and a positive effect oncardiac remodeling, leading to adecrease in collagen density andan increase in capillary density.In addition, recent evidence indi-cates that the If current may be reexpressed in animal and humanventricular myocytes from failinghearts and may have an arrhyth-mogenic role. If inhibition wouldthus exert an antiarrhythmic effectin heart failure, but this hypothesisremains to be proven in the clinicalsetting.

SELECTED ABBREVIATIONSAND ACRONYMS

CIBIS II Second Cardiac Insufficiency BIsoprolol Study

DCM dilated cardiomyopathy

HCN hyperpolarization-activated cyclic nucleotide–gated cation channel

ICM ischemic cardio-myopathy

LVH left ventricular hypertrophy

MERIT-HF MEtoprolol controlled-release Randomized Intervention Trial in Heart Failure

SHR spontaneously hypertensive rat


tractility. This improvement wascompletely prevented by chronicpacing at a rate equal to the pre-treatment heart rate.

The importance of heart rate reduc-tion per se was evaluated in post-hoc analyses of the major clinicaltrials testing the effects of β-blockersin heart failure. In the MEtoprololcontrolled-release Randomized Intervention Trial in Heart Failure(MERIT-HF), two dosage subgroupswere compared, one receiving morethan 100 mg metoprolol CR/X twice

daily (n=1202) and the other receiv-ing 100 mg or less (n=412) duringthe first 3 months of follow-up.6

Heart rate was reduced to a similardegree in both groups. The reduc-tion in total mortality with metopro-lol CR/XL versus placebo was similarin both groups (38%). This may indicate a higher sensitivity to β-blockade in the low-dose group,but it may also suggest that themain benefit of β-blockade resultedfrom its effect on heart rate.

The Second Cardiac InsufficiencyBIsoprolol Study (CIBIS II) evaluatedthe relationship between baselineheart rate changes 2 months afterthe beginning of treatment andoutcomes (mortality and hospital-ization for heart failure).7 Multivari-ate analyses showed that, in addi-tion to β-blocker treatment, bothbaseline heart rate and changes at2 months significantly correlatedwith survival and hospitalization forworsening of heart failure. Further-more, the lowest baseline heart rateand the greatest heart rate reduction

were associated with better survivaland a greater reduction in hospitaladmissions. These results were in-terpreted as confirming the hypoth-esis that heart rate reduction per sein patients with heart failure is asso-ciated with improved survival. Thisresult is possibly the consequenceof the induced reduction in ische-mia, which is present to differentdegrees in dilated ventricles even inthe absence of coronary artery dis-ease.8 The benefit of bisoprolol was

not significant in patients with atrialfibrillation. It was observed thatamong these patients, those treat-ed with β-blockers and who subse-quently died, had a more importantdecrease in blood pressure, sug-gesting that the marked decrease inblood pressure induced by β-blockertreatment may be deleterious. Thiseffect is not expected with drugsinhibiting the If channels.

Conflicting results have been re-ported in studies investigating theeffects of carvedilol in heart failurepatients. Post-hoc stratification ofpatients in the US–Carvedilol heartfailure program into groups aboveand below the mean baseline heartrate showed that the mortality ben-efit of carvedilol compared withplacebo was only significant in thegroup with a high baseline heartrate.9 Others have not found sucha relationship. In a retrospective,observational, single-center studyaimed at determining whether theprocess of reverse remodeling inresponse to carvedilol in heart fail-ure patients was dependent onbaseline heart rate and on β-block-ade–induced heart rate reduction,no relationship was found betweenleft ventricular size and left ventric-ular function and heart rate, eitherat baseline or after β-blockade.10

This suggests that the remodelingprocess may also be controlled bymechanisms other than heart rate.

Recent experimental and clinicalfindings consistently indicate thatthe heart rate reduction induced byivabradine may be beneficial in pa-tients with left ventricular dysfunc-tion. The effects of long-term heartrate reduction on left ventricularfunction and remodeling was inves-tigated in a rat model of heart fail-ure.11 The animals randomized toivabradine, exhibited long-term (90days) heart rate reduction. In theseanimals, treatment with ivabradine

31


Can If inhibition help in congestive heart failure? - Tavazzi and Mugelli

Change in heart rate (bpm)

Cha

nge

in m

orta

lity

60

–60

–80

–100

0

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–18 –16 –10 –8 –4

US CARVEDILOLMOCHA

NORTIMOLOL

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PROFILE

VHeFT(prazosin)

VHeFT(HDZ/ISDN)ANZ

GESICA

–20

20

40

–14 –12 –6 2 4 8–2 0 6

Figure 1. Relationship between changes in heart rate and mortality in congestive heart failure (CHF).In patients with heart failure changes in mortality with a variety of drug regimens in different trialsare related to changes in heart rate. Only trials in the lower left quadrant had reduced heart rate andmortality.

Adapted from reference 2: Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heartfailure. Eur Heart J. 1999;1(suppl H):H64-H69. Copyright © 1999, Oxford University Press.

32

resulted in improved left ventricularfunction compared with placebo,and stroke volume was increased,thereby preserving cardiac output.Changes in ventricular structurewere also reported, with a decreasein left ventricular collagen densityand an increase in capillary density,without any change in left ventricu-lar weight. The mechanisms of thesestructural and functional cardiacchanges are still speculative. Heartbeating is metabolically costly.Moreover, elevated heart rate short-ens the diastolic intervals duringwhich the coronary blood flow per-fuses the myocardium and providesthe myocytes with nutrients andoxygen and carries away the termi-nal products of cellular metabolism.Relative hypoxia in the subendocar-dial layers can also induce endothe-lial dysfunction, triggering the re-lease of cytokines and free radicals.

In a 3-month randomized double-blind placebo-controlled clinicalstudy,12 ivabradine was administeredat a dosage of 10 mg twice daily ontop of conventional therapy (exceptβ-blockers) to 56 patients with coro-nary artery disease and mild-to-moderate congestive heart failure.Patients with the highest degree ofleft ventricular systolic dysfunction(echographic left ventricular ejec-tion fraction [EF] <35%) demonstrat-ed a mean 5% increase in EF withivabradine, compared with a mean0.5% decrease in patients receivingplacebo.

Several data support ivabradine’ssafety in the elderly population. Apharmacokinetic analysis performedin elderly patients showed thatthere were no differences in phar-macokinetics (AUC and Cmax) be-tween elderly (>65 years) and veryelderly patients (>75 years) and theoverall population.13 In contrast, β-blockers are contraindicated inpatients with obstructive lung dis-

eases, decompensated conditions,hypotension, and atrioventricularconduction disturbances, as listedby a retrospective study assessingβ-blocker utilization patterns in clin-ical practice setting.14 Similar find-ings were observed in a nationwideobservational study performed inItaly.15 Moreover, in patients inwhom β-blocker therapy needed tobe uptitrated to the maximum tol-erated dose, the dose administeredwas frequently lower than the rec-ommended dose.16,17 β-Blocker usemay also be hampered by the oc-currence of fatigue, hypotension,dizziness, and dyspnea, requiringdiscontinuation of treatment. Thus,though β-blockers are very effectivein heart failure patients, a numberof contraindications and poor tol-erability may in practice restricttheir use at the full dosage provento be effective in clinical trials.

Ivabradine can be combined withall the drugs currently recommend-ed for use in heart failure patientswithout any risk of untoward druginteractions developing. Thus, nokinetic or dynamic interactions withivabradine were observed in patientsof pivotal phase 3 studies receivingangiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists, diuretics, aspirin, digox-in, amiodarone, or cholesterol-low-ering agents. No clinically significantchanges in atrioventricular conduc-tion, QT interval, and myocardialcontractility have been reported.Therefore, combination of ivabra-dine and β-blockers or other heartrate–lowering agents does not posespecific problems. Thus, it appearsthat patients with coronary arterydisease and left ventricular systolicdysfunction may benefit from heartrate reduction with ivabradine what-ever the background therapy, includ-ing or not β-blockers. Ivabradine is currently being tested in a largeinternational phase 3 trial—the

MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction(BEAUTIFUL).

POTENTIAL CLINICAL EFFECTS OF If INHIBITION

IN NONPACEMAKER CARDIAC CELLS

In addition to the benefit of If inhi-bition in regard of the pacemakercells of the atrioventricular node,discussed above, If inhibition mayalso be of benefit in heart failurethrough a different mechanism ofaction, by acting on the reexpressionof the If current in the ventricularcells of the failing heart.

Whereas the role of If in the gener-ation of spontaneous sinus nodeactivity and in the control of heartrate is widely documented and hasbeen known for a long time,18,19 thepresence of If in ventricular myo-cytes is a more recent and quite in-triguing finding. First of all, it mustbe stressed that the presence of If

in ventricular myocytes relates topathophysiology rather than physi-ology. The first recording of If inventricular cardiomyocytes was re-ported in 1993 in the normal guineapig. The characteristics of this If

current were such that they ruledout any possible physiological rolein the ventricle, because it was muchsmaller than the If current recordedin pacemaker cells, and was acti-vated at negative voltages far belowthe values of normal resting po-tentials, (ie, more negative than–100 mV).20 However, in the settingof heart disease, the situation isvery different. This is because, invarious animal models of cardiachypertrophy and failure, If has beenshown to be upregulated,21-23 tothe extent that it may assume afunctional role. It was found thatduring the recording of the intracel-



lular electrical activity of papillarymuscles isolated from 18-month-oldspontaneously hypertensive rats(SHR), ie, rats with a severe cardiachypertrophy, the diastolic phase wasnot flat but a “sort” of diastolic de-polarization could be detected be-tween two driven action potentials.24

The papillary muscles isolated fromold SHR were also particularly sen-sitive to the arrhythmic action ofisoprenaline, a β-adrenergic agonist.It seemed obvious to conclude thatone of the reasons for this enhancedsusceptibility to the arrhythmogenicaction of the catecholamines couldbe due to the “unusual” presenceof that “unusual” diastolic depolar-ization. The presence of If was sub-sequently documented in ventricularmyocytes isolated from the heartof animals with different degrees ofcardiac hypertrophy. The degree ofhypertrophy was positively correlat-ed with an increased If density,22

and changes in expression levelswere most pronounced in thosecardiac regions with the highestoverload,25,26 indicating that theprocesses leading to hypertrophydirectly affected the level of hyper-polarization-activated cyclic nu-cleotide-gated cation channel (HCN)expression, which are the molecularcomponents of native f-channels.27

Four HCN genes were identified,encoding different proteins, whichassemble to form tetrameric (ho-momeric or, likely, heteromeric)compounds.

Figure 2A shows If current record-ings obtained in ventricular myo-cytes isolated from normal humanheart (human donor heart not usedfor transplantation because of tech-nical problems) and in myocytesisolated from a human heart ex-planted because of terminal failure.Figure 2B summarizes the relativeincrease in "current density," com-paring diseased vs control ventricu-lar cardiomyocytes, in several rat

models of cardiomyopathies and inhuman ischemic and dilated car-diomyopathies. "Current density"designates a current amplitude thatis normalized with respect to cellsize: since the cardiomyocytes are“hypertrophic,” ie, enlarged, in car-diomyopathies, it is absolutely nec-

essary to correct the current ampli-tude for cell dimensions. If densityis markedly increased in left ven-tricular cardiomyocytes from ratswith moderate or severe cardiachypertrophy (LVH) caused by pres-sure overload (PO), and is evengreater in rats with overt heart fail-ure (HF) consequent to high blood

pressure (PO) or post–myocardialinfarction (PMI). In addition toelectrophysiological data, molecu-lar biology techniques allowed todemonstrate a parallel upregulationof the HCN2 and HCN4 mRNA lev-els, which are the predominant iso-forms underlying ventricular If .28

Recordings of If in ventricular myo-cytes show electrophysiologicalproperties (voltage-dependence,kinetics of activation, Na/K perme-ability ratio) qualitatively similarto those described 20 years ago byDiFrancesco (as reviewed in refer-ence 29) for primary and subsidiarypacemakers. It has been proposed

3333



I f ov

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isea

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B

Figure 2. Ventricular If expression is increased in cardiomyopathies. Panel A: Typical example of If

recorded in ventricular myocytes isolated from normal or failing heart. Panel B: Each histogram rep-resents the ratio between current density measured in ventricular cardiomyocytes from rat or humandiseased hearts, and respective controls (indicated by the dashed line); bars are confidence intervals(95%). LVH-moderate and LVH-severe: relative increase in If in rats with moderate or severe left ven-tricular hypertrophy caused by aortic banding23 or long-lasting pressure overload (PO),22 respectively.PO-HF, PMI-HF: relative increase of If in rats with overt heart failure (HF), resulting from uncom-pensated hypertrophy due to pressure overload (PO-HF)22 or post–myocardial infarction (PMI-HF)due to coronary ligation,25,26 respectively. DCM, ICM: relative increase of If in left ventricular myocytesisolated from the explanted heart of patients undergoing cardiac transplantation for terminal dilatedcardiomyopathy (DCM) or ischemic cardiomyopathy (ICM).34 For all conditions, the relative increasein If density was statistically significant versus controls, ie, normotensive rats, sham-operated rats, ornondiseased donor hearts not transplanted for technical reasons, with the exception of DCM patients(NS: not significant).



34

that mislocalized expression and/oroverexpression of cardiac HCNchannels may represent an exampleof a general phenomenon, calledcardiac remodeling, which consistsnamely in the reexpression of fetalproteins: in fact, f-channels are pres-ent in fetal or neonatal ventricularmyocytes,30,31 which lose their ca-pacities of generating spontaneousactivity during electrophysiologicalmaturation toward adult pheno-type. However, from a clinical pointof view, the most interesting aspectof this phenomenon is that If mayrepresent an arrhythmogenic mech-anism in heart failure, which is acondition associated with high riskfor sudden cardiac death. Furthersupport for this hypothesis comesfrom the evidence of If expressionin the failing human ventricle fromexplanted hearts.32,33 Correlationwith the severity of cardiac diseasewas obviously impossible in thissetting, as all patients had terminalheart failure. However, a fascinatingfinding was that changes in If den-sity correlated with the etiology ofthe disease, and, for example, If

overexpression was greater in is-chemic cardiomyopathy (ICM) thanin idiopathic dilated cardiomyopa-thy (DCM) (Figure 2).34 Recent mo-lecular findings have shown thatHCN2 and HCN4 expression at bothmRNA and protein levels is marked-ly increased in samples obtainedfrom hearts explanted from patientswith ICM, providing a molecularexplanation for the functional up-regulation of If in heart failure.35

The signaling pathways leading toenhancement of If in nonautomaticregions of the heart are not fullyclarified, but the renin-angiotensinsystem seems to play a pivotalrole.36,37 Overall, these studies rep-resent the first evidence in favor ofan altered If expression in cardiacdiseases and suggest its potentialrole in the associated abnormalelectrical activity.

CONCLUSIONS

The molecular identification of HCNsubunits and their functional/mo-lecular detection in the diseasedventricle have resulted in an unfore-seeable surge of interest for pace-maker channels. Based on thesenew findings, it appears that selec-tive f-channel inhibitors such asivabradine, in addition to selectiveheart rate reduction (which in itselfmay be beneficial in patients withleft ventricular dysfunction and heartfailure), may also block the If currentexpressed in ventricular myocytesof the failing heart (where it mayrepresent an arrhythmogenic trig-ger), and thus reduce the risk ofsudden death—an exciting prospectthat still awaits clinical confirmation.

REFERENCES

1. Borer JS, Fox K, Jaillon P, et al.

Anti-anginal and anti-ischemic effects ofivabradine, an If inhibitor in stable angina:a randomized, double blinded, multicenter,placebo-controlled trail.

Circulation. 2003;107:817-823.

2. Kjekshus J, Gullestad L.

Heart rate as a therapeutic target in heartfailure.


3. Swedberg K, Eneroth P, Kjekshus J,et al.

Hormones regulating cardiovascular func-tion in patients with severe congestive heartfailure and their relation to mortality.CONSENSUS Trial Study Group.

Circulation. 1990;82:1730-1736.

4. Nul DR, Doval HC, Grancelli HO,et al; GESICA-GEMA Investigators.

Heart rate is a marker of amiodarone mor-tality reduction in severe heart failure.

J Am Coll Cardiol. 1997;29:1199-1205.

5. Nagatsu M, Spinale FG, Koide M,et al.

Bradycardia and the role of beta-blockade inthe amelioration of left ventricular dysfunction.

Circulation. 2000;101:653-659.

6. Wikstrand J, Hjalmarson A, Waagstein F, et al.

Dose of metoprolol CR/KL and clinical out-comes in patients with heart failure.

J Am Coll Cardiol. 2002;40:491-498

7. Lechat P, Hulot JS, Escolano S, et al.

Heart rate and cardiac rhythm relationshipswith bisoprolol benefit in chronic heart failure in CIBIS II trial.

Circulation. 2001;103:1428-1433.

8. Unverferth DV, Magorien RD,Lewis RP, et al.

The role of subendocardial ischemia in per-petuating myocardial failure in patients withnon-ischemic congestive cardiomyopathy.

Am Heart J. 1983:105:176-179.

9. Packer M, Bristow MR, Cohn JN,et al.

The effect of carvedilol on morbidity and mor-tality in patients with chronic heart failure.US Carvedilol Heart Failure Study Group.

N Engl J Med. 1996;334:1349-1355.

10. Arnold RH, Kotlyar E, Hayward C,et al.

Relation between heart rate, heart rhythm, andreverse left ventricular remodelling in re-sponse to carvedilol in patients with chronicheart failure: a single centre, observationalstudy.

Heart. 2003;89:293-298.

11. Mulder P, Barbier S, Chagraoui A,et al.

Long term heart rate reduction induced bythe selective If current inhibitor ivabradineimproves left ventricular function and in-trinsic myocardial structure in congestiveheart failure.

Circulation. 2004;109:1674-1679.

12. Jondeau G, Korewicki J, Vasilianskas D.

Effect of ivabradine in patients with leftventricular systolic dysfunction and coro-nary artery disease.

Eur Heart J. 2004;25(suppl):451. Abstract 2637.

35



13. Pharmacokinetics of Ivabradine.

Summary of Product Characteristics.London, UK: EMEA; 25 October 2005.

14. Gupta R, Wilson Tang WH, YoungJB.

Patterns of beta-blocker utilization in patientswith chronic heart failure: experience froma specialized outpatient heart failure clinic.

Am Heart J. 2004;147:79-83.

15. Maggioni AP, Sinagra G, OpasichC, et al.

Treatment of chronic heart failure with betaandrenergic blockade beyond controlledclinical trials: the BRING-UP experience.

Heart. 2003;89:299-305.

16. Sin DD, Mc Alister FA.

The effects of beta-blockers on morbidity andmortality in a population-based cohort of11,942 elderly patients with heart failure.

Am J Med. 2002;113:650-656.

17. Di Lenarda A, Scherillo M, Maggioni, et al; TEMISTOCLE Investigators.

Current presentation and management ofheart failure in cardiology and internalmedicine hospital units: a tale of two worlds.The TEMISTOCLE study.

Am Heart J. 2003;146:e12.

18. Noma A, Irisawa H.

Membrane currents in the rabbit sinoatrialnode cell as studied by the double micro-electrode method.

Pflugers Arch. 1976;364:45-52.



Nature. 1979;280:235-236.

20. Yu H, Chang F, Cohen IS.

Pacemaker current exists in ventricular myocytes.

Circ Res. 1993;72:232-236.

21. Cerbai E, Barbieri M, Mugelli A.

Characterization of the hyperpolarization-activated current, If , in ventricular myocytes isolated from hypertensive rats.

J Physiol (Lond). 1994;481:585-591.

22. Cerbai E, Barbieri M, Mugelli A.

Occurrence and properties of the hyperpolar-ization-activated current If in ventricularmyocytes from normotensive and hyperten-sive rats during aging.

Circulation. 1996;94:1674-1681.

23. Stilli D, Sgoifo A, Macchi E, et al.

Myocardial remodeling and arrhythmogene-sis in moderate cardiac hypertrophy in rats.

Am J Physiol-Heart Circ Physiol.2001;280:H142-H150.

24. Barbieri M, Varani K, Cerbai E, et al.

Electrophysiological basis for the enhancedcardiac arrhythmogenic effect of isoprenalinein aged spontaneously hypertensive rats.

J Mol Cell Cardiol. 1994;26:849-860.

25. Fernandez-Velasco M, Goren N,Benito G, Blanco-Rivero J, Bosca L,Delgado C.

Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channelmRNA expression in ventricular cells fromcontrol and hypertrophied rat hearts.

J Physiol (Lond). 2003;553:395-405.

26. Sartiani L, Cerbai E, DePaoli P,et al.

The expression and pharmacological modu-lation of the pacemaker current in ventricularmyocytes from post myocardial infarction.

Circulation. 2000;102:129.

27. Biel M, Schneider A, Wahl C.

Cardiac HCN channels: structure, function,and modulation.


28. Shi W, Wymore R, Yu H, et al.

Distribution and prevalence of hyperpolariza-tion-activated cation channel (HCN) mRNAexpression in cardiac tissues.

Circ Res. 1999;85:e1-e6.

29. Accili EA, Proenza C, Baruscotti M,DiFrancesco D.

From funny current to HCN channels: 20 years of excitation.

News Physiol Sci. 2002;17:32-37.

30. Cerbai E, Pino R, Sartiani L,Mugelli A.

Influence of postnatal-development on If

occurrence and properties in neonatal ratventricular myocytes.


31. Yasui K, Liu W, Opthof T, et al.

If current and spontaneous activity inmouse embryonic ventricular myocytes.

Circ Res. 2001;88:536-542.

32. Cerbai E, Pino R, Porciatti F, et al.

Characterization of the hyperpolarization-ac-tivated current, If , in ventricular myocytesfrom human failing heart.

Circulation. 1997;95:568-571.

33. Hoppe UC, Jansen E, Sudkamp M,Beuckelmann DJ.

Hyperpolarization-activated inward currentin ventricular myocytes from normal andfailing human hearts.

Circulation. 1998;97:55-65.

34. Cerbai E, Sartiani L, DePaoli P,et al.

The properties of the pacemaker current If inhuman ventricular myocytes are modulatedby cardiac disease.


35. Lonardo G, Stillitano F, Zicha S,Cerbai E, Mugelli A, Nattel S.

Molecular basis of funny current (If ) in normal and failing human heart.

Circulation. 2004;110(suppl)III129.

36. Cerbai E, Crucitti A, Sartiani L,et al.

Long-term treatment of spontaneously hyper-tensive rats with losartan and electrophysi-ological remodeling of cardiac myocytes.


37. Cerbai E, De Paoli P, Sartiani L,Lonardo G, Mugelli A.

Treatment with irbesartan counteracts thefunctional remodeling of ventricular myocytesfrom hypertensive rats.

Cardiovasc Pharmacol. 2003;41:804-812.

36

Can If inhibition help after myocardial infarction?Guillaume Martin, MD; Jean-Claude Tardif, MD, FRCPC, FACC

Department of Medicine - Montreal Heart Institute - Montreal - CANADA

Ivabradine is a selective and specif-ic If channel inhibitor with provenantianginal and anti-ischemicproperties, but without effects onblood pressure, myocardial contrac-tility, and atrioventricular (AV)node conduction. These advantagesplace ivabradine in a unique posi-tion to reduce heart rate in unstablepatients. Contraindications to theuse of �-blockers in patients withacute MI represent additional po-tential indications for ivabradine.Moreover, ivabradine improves myo-cardial stunning following ischemiabetter than �-blockade. Ivabradinemay also be helpful in patients withresidual angina or ischemia inwhom �-blockers should be avoidedand in those not tolerating themwell. In the longer-term follow-up,evidence suggests that reducingheart rate could prevent progres-sion of atherosclerosis and plaquerupture. Ivabradine may thereforebecome very helpful in the manage-ment of patients after myocardialinfarction.

Keywords: If current; myocardial infarction;stunning; heart rate; angina; atherosclerosis;ivabradineAddress for correspondence:Jean-Claude Tardif, MD, Montreal Heart Institute,5000 Belanger Street, Montreal, H1T 1C8 Canada(e-mail: [email protected])


HEART RATE, MYOCARDIAL INFARCTION,

AND MORTALITY

any large observationalstudies have shown alink between increasedheart rate and all-cause

mortality and cardiovascular eventsin patients with hypertension, withmetabolic syndrome, and in theelderly.1-3 Recently, we have assessedthe relationship between restingheart rate and future cardiovascularevents in a population of 25000patients with suspected or provencoronary artery disease (CAD).4

Over a median follow-up of 14.7years, resting heart rate was a pre-dictor of overall and cardiovascularmortality, independent of otherknown risk factors such as hyperten-sion, diabetes, and smoking. Thesize of the study also allowed ad-justment of the multivariable modelfor the extent of CAD and left ven-tricular ejection fraction. Restingheart rate was an independent riskfactor for total and cardiovascular

mortality, even after adjusting forsuch covariates. A high resting heartrate (≥83 bpm) was indeed a strongpredictor of total and cardiovascu-lar mortality (hazard ratios of 1.32and 1.31, respectively). In addition,resting heart rate was a risk factorfor time to cardiovascular rehospi-talizations.

Several studies conducted beforethe thrombolysis era have demon-strated that a high heart rate duringhospitalization increases overallmortality up to 2 years after myo-cardial infarction.5 In patients withno or mild heart failure, mortalitywas more than doubled (P<0.001)for patients with heart rate >90/minversus those with <90/min. Disegniet al6 reported similar results in1044 patients who survived an acutemyocardial infarction. Overall mor-tality was 4.3%, 8.7%, 11.8% for pa-tients with discharge resting heartrate <70/min, 70 to 90/min, >90/min,respectively. For patients withoutclinical signs of heart failure duringhospitalization, 1-year mortality was

M


SELECTED ABBREVIATIONS AND ACRONYMS

AV atrioventricular

BEAUTI fUL MorBidity-mortality EvAlUaTion of the If inhibitor ivabradinein coronary disease and left ventricULar dysfunction

CAD coronary artery disease

COPD chronic obstructive pulmonary disease

GISSI-2 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–2

INITIATIVE INternatIonal TrIal of the AnTianginal effects of IVabradinE compared to atenolol


37

2.8%, 5.1%, 6.6% for patients withdischarge resting heart rate <70/min,70 to 90/min, >90/min, respectively.A retrospective analysis of datafrom the Gruppo Italiano per lo Stu-dio della Sopravvivenza nell'InfartoMiocardico–2 (GISSI-2) study inpatients thrombolyzed for acutemyocardial infarction was also pub-lished.7 The overall 6-month mor-tality was 0.8% for those with a dis-charge heart rate below 60 beats/minand 14.3% for those with a heartrate above 100 beats/min. Restingheart rate remained an independentprognostic factor in a multivariableanalysis.

These data demonstrate a stronglink between heart rate and cardio-vascular morbidity and mortality. Inaddition, whereas agents that in-duce tachycardia have been found tohave neutral or deleterious effectson mortality, several of those thatreduce heart rate have been shownto improve survival. The relationshipbetween reduction in heart rate anddecrease in mortality has indeedbeen well established with β-block-ers after myocardial infarction andin patients with heart failure.8

If CHANNEL INHIBITIONDURING IN-HOSPITAL

COURSE AFTER MYOCARDIAL INFARCTION

Patients with acute myocardial in-farction generally benefit from heartrate reduction both through a de-crease in myocardial oxygen require-ment and a lengthening in the duration of diastole and myocardialperfusion. However, the negativeinotropic and hypotensive effects ofβ-blockers contraindicate their usein patients with pulmonary conges-tion, borderline blood pressure,overt pulmonary edema, or cardio-genic shock. Ischemic left ventriculardysfunction is also often accompa-nied by diastolic dysfunction. Be-

cause excessive tachycardia hasdeleterious consequences on dias-tolic function, heart rate reductionis important to achieve. However,the negative lusitropic effects of β-blockers may represent anotherdisadvantage in this setting. Aspreviously explained in this issue,ivabradine provides selective, re-versible and use-dependent If chan-nel inhibition. The If current locatedin the sinus node has a major influ-ence on slow diastolic depolariza-tion. Ivabradine therefore offerspure heart rate reduction withoutaffecting hemodynamic parameterssuch as ejection fraction, bloodpressure, contractility, atrioventric-ular conduction, or coronary vaso-motion. The absence of effects onmyocardial contractility and bloodpressure places ivabradine in aunique position to control heartrate in unstable patients.

Although β-blockers have severalside effects, bronchospasm and atri-oventricular (AV) block constitutethe most relevant adverse reactionsthat limit their use in the emergencysetting. While asthma or chronic ob-structive pulmonary disease (COPD)represent only relative contraindi-cations to β-blockade, some patientsclearly develop bronchospasm andwheezing with β-blockers, whichrequire dose reduction or abruptwithdrawal. Such patients who re-quire heart rate reduction wouldclearly benefit from the lack of thisside effect with ivabradine.

IVABRADINE POST-DISCHARGE AFTER

MYOCARDIAL INFARCTION

The role of ivabradine in the treat-ment of patients discharged follow-ing a myocardial infarction musttake into account several consider-ations: (i) the prognostic value ofresting heart rate and the relation-ship between heart rate reduction

and decrease in mortality after myocardial infarction shown withβ-blockers; (ii) several patients haveresidual angina and/or ischemia after myocardial infarction even ifthey undergo revascularization; (iii) side effects such as fatigue, de-pression, and sexual dysfunctionmay limit long-term compliance toβ-blockers; and (iv) ivabradine hasshown antianginal and anti-ischemicproperties9 that are not inferior tothose of the β-blocker atenolol.10 Itis particularly relevant to note thatmore than half of the 939 patientsinvolved in the INternatIonal TrIalof the AnTianginal effects of IVabra-dinE compared to atenolol (INITIA-TIVE)10 (see other article in this issue) had previously suffered a my-ocardial infarction.

Ivabradine shares with β-blockersthe property of decreasing heartrate and oxygen demand from theischemic heart, which is presum-ably fundamentally important inmediating anti-ischemic effects. Inaddition, Colin et al11 compared theeffects of ivabradine, atenolol, andplacebo on oxygen consumptionand supply during exercise in dogs.For a given heart rate, left ventricu-lar ejection time was longer withatenolol than with ivabradine be-cause of the negative inotropic ef-fects of atenolol. As a consequence,the increase in diastolic time andcoronary blood flow was greaterwith ivabradine than with atenolol(Figures 1 and 2, next page).11 Fur-thermore, in contrast to β-blockers,ivabradine has also been shown notto limit the decrease in coronaryresistance induced by exercise.12

Given the absence of cardiac effectsother than exclusive heart rate low-ering, ivabradine is suitable aftermyocardial infarction for patientswith residual angina or ischemia inwhom β-blockers should be avoid-ed (those with AV block, peripheralvascular disease, and COPD) and


Can If inhibition help after myocardial infarction? - Martin and Tardif

38

for those not tolerating well β-block-ers or calcium antagonists. Unlikeβ-blockers, ivabradine may be usedin vasospastic angina because itdoes not increase coronary vaso-motor tone.

In addition to the side effects of β-blockers, which include depres-sion, fatigue, and cold extremities,erectile dysfunction is a particular-ly important problem associatedwith their use in middle-aged men.

Ivabradine may therefore be veryuseful in such patients. The fact thatasthma and COPD represent relativecontraindications to β-blockade hasbeen mentioned previously. How-ever, some patients with both CADand COPD develop angina whentreated with inhaled β-adrenergicagonists because of the resultingtachycardia. The heart rate reductionobtained with ivabradine could bevery helpful in this setting. Patientscan also have variable degrees ofAV block after myocardial infarctionthat develop or are exacerbated withβ-blockers. The need for selectiveheart rate reduction in patients withmyocardial ischemia and AV-nodeconduction abnormalities repre-sents another excellent indicationfor ivabradine. This is particularlyrelevant for older patients with aprolonged PR interval.

If CURRENT INHIBITIONAND LIMITATION OF

MYOCARDIAL STUNNING

Postischemic myocardial dysfunc-tion, or myocardial stunning, canresult in systolic and/or diastolicventricular dysfunction in differentsettings, such as at the time of re-perfusion after myocardial infarction,but also after periods of ischemiain patients with chronic angina.Monnet et al13 demonstrated thebenefit of ivabradine on myocardialstunning in dogs compared withatenolol and placebo. Ivabradine isbetter than placebo and atenololfor time to recovery of myocardialcontractility after exercise-inducedstunning, and this holds truewhether the drugs were infused be-fore or after exercise (Figure 3).13

Under atrial pacing, the negativeeffects of atenolol on systolic func-tion during stunning were amplified(Figure 4).13 These results demon-strate that ivabradine enhances re-covery of myocardial stunning afterexercise-induced ischemia in dogs,



Baseline Rest Paced rest Exercise Paced exercise

(mL

/min

)

90

80

70

40

20

30

10

0

50

60§

§¶

§¶

Saline

Ivabradine

Atenolol

Mean coronary blood flow

Figure 1. Effects of ivabradine, atenolol and placebo on mean coronary blood flow (ml/min) at base-line, rest, and exercise. §P<0.05: significantly different from saline. ¶P<0.05: ivabradine significantlydifferent from atenolol.

Modified from reference 11: Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate andcontractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol.2003;284:H676-H682. Copyright © 2003, American Physiological Society.

Baseline Rest Paced rest Exercise Paced exercise

(mL O

2/m

in)

10

9

8

5

2

4

1

0

3

6

7 §

§¶

§¶

Saline

Ivabradine

Atenolol

Myocardial oxygen consumption

Figure 2. Effects of ivabradine, atenolol and placebo on myocardial consumption (mL O2/min) atbaseline, rest, and exercise. Atrial pacing inhibits heart rate–lowering of drugs. §P<0.05: significantlydifferent from saline. ¶P<0.05: atenolol significantly different from ivabradine.

Modified from reference 11: Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate andcontractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol.2003;284:H676-H682. Copyright © 2003, American Physiological Society.

39



whereas atenolol has deleteriouseffects, explained by its negativeinotropic properties. Thus, ivabra-dine has the potential to improvemyocardial stunning in patientswith ischemic heart disease.

HEART RATE ANDATHEROSCLEROSIS

PROGRESSION: A TARGETFOR If INHIBITION?

Secondary prevention is central tothe therapeutic strategy after dis-charge following myocardial infarc-tion. Prevention of atherosclerosisprogression and stabilization ofplaque are indeed of paramount im-portance to prevent recurrent clinicalevents in the long-term follow-up.Heart rate is significantly correlatedwith the severity and progressionof atherosclerosis on coronary an-giography among men who had developed myocardial infarction ata young age.14 Experimental datahave also demonstrated that a re-duction in heart rate can delay theprogression of coronary atheroscle-rosis in monkeys.15,16 Beere et alshowed that male cynomolgus mon-keys subjected to sinus node abla-tion or those with innately low heartrates had significantly less coronaryatherosclerosis than did animalswith higher heart rates.15 Atheroscle-rosis was also inhibited when car-diac responses to stress were inhib-ited in monkeys fed an atherogenicdiet.16 Stress-related tachycardiahas been used to investigate themechanisms of enhanced atheroge-nesis at high heart rates. The pro-portion of dysfunctional coronaryartery endothelial cells in monkeysexposed to behavioral stress wasmuch higher in untreated, tachy-cardic animals than in those treatedwith a β-blocker.17 This coronaryartery endothelial dysfunction asso-ciated with high heart rates, whichwas also observed by Skantze et al,18

may represent an important mech-

anism of increased atherogenesis.These observations are supportedby results from the Beta-blockerCholesterol-lowering Asymptomat-ic Plaque Study (BCAPS)—a ran-domized trial that showed that a

β-blocker reduced the rate of pro-gression of carotid-intima thick-ness in asymptomatic patients.19

More recently, positive associa-tions have been identified betweenplaque disruption, an elevated left

Ch

an

ge

in

w

all

th

ick

en

ing

(%

)

B2B1 Ex 10' 30' 1h 2h 3h 4h 5h 6h

40

20

0

–20

–80

–100

–60

–40

****

*

*

*

*†

*†*†

*†*†*†*†

*†

Figure 3. Evolution of wall thickening in the ischemic zone (% change from base 1) before (B1)and after (B2) administration of ivabradine (open circles), saline (full circles) or atenolol (opentriangles). All recordings were performed at spontaneous heart rate. *P<0.05: significantly different from saline. †P<0.05: atenolol significantly different from ivabradine.

Modified from reference 13: Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF,Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning.Eur Heart J. 2004;25:579-586. Copyright © 2004, Oxford University Press.

Ch

an

ge

in

w

all

th

ick

en

ing

(%

)

B2B1 Ex 10' 30' 1h 2h 3h 4h 5h 6h

40

20

0

–20

–80

–100

–60

–40

*†

*†*†*†*†*†

*†

*†

Figure 4. Evolution of wall thickening in the ischemic zone (% change from base 1) before (B1)and after (B2) administration of ivabradine (open circles), saline (full circles) or atenolol (opentriangles). Recordings at baseline and during the recovery period were performed under atrialpacing at 150/min. *P<0.05: significantly different from saline. †P<0.05: atenolol significantlydifferent from ivabradine.

Modified from reference 13: Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF,Berdeaux A. Heart rate reduction during exercise-induced myocardial ischaemia and stunning.Eur Heart J. 2004;25:579-586. Copyright © 2004, Oxford University Press.

40



ventricular mass, and a mean heartrate >80 beats/min, while a negativeassociation with the use of β-block-ers was also shown. Specifically, amean heart rate >80 beats/min wasan independent predictor of athero-sclerotic plaque disruption with anodds ratio of 3.19 in a multivariableanalysis.20 Ivabradine may there-fore improve patient outcomes aftermyocardial infarction by reducingatherosclerotic progression and bypreventing plaque rupture.

CONCLUSION

A high resting heart rate is a strongpredictor for cardiovascular mortali-ty and morbidity in patients withCAD. Heart rate reduction is an in-tegral part of an optimal pharma-cological strategy to restore thebalance between myocardial oxygendemand and supply, both througha decrease in myocardial oxygen re-quirement and a lengthening in theduration of diastole and myocardialperfusion. Early after myocardialinfarction, the negative inotropicand hypotensive effects of β-block-ers contraindicate their use in pa-tients with pulmonary congestion,borderline blood pressure, overtpulmonary edema, or cardiogenicshock. Following discharge after my-ocardial infarction, β-blockers havetraditionally been considered as afirst-line therapy, but their use maybe limited by side effects includingfatigue, depression, and sexual dys-function. Bronchospasm and atrio-ventricular block represent other

limitations of β-blockers. Ivabradineis a selective and specific If inhibitorwith proven antianginal and anti-is-chemic effects that have been shownto be noninferior to those of the β-blocker atenolol. Unlike β-block-ers, ivabradine is devoid of intrinsicnegative inotropic effects and doesnot affect coronary vasomotion; ithas no effects on blood pressure,myocardial contractility and AVnode conduction. These advantagesplace ivabradine in a unique posi-tion to reduce heart rate in unstablepatients. In addition, a whole rangeof patients with CAD may benefitfrom exclusive heart rate reductionwith ivabradine, including thosewith contraindications or intoleranceto the use of β-blockers, such aspatients with bronchospasm and AVblock, and patients that are insuffi-ciently controlled by β-blockers orcalcium channel blockers. Ivabradinehas also been shown to improvemyocardial stunning after myocar-dial ischemia more effectively thanβ-blockade. Furthermore, evidencesuggests that reducing heart ratecould prevent the progression ofatherosclerosis as well as plaquerupture. The value of ivabradine forreduction of hard cardiovascularevents in patients with ischemicheart disease will be tested in theMorBidity-mortality EvAlUaTion ofthe If inhibitor ivabradine in patientswith coronary disease and left ven-tricULar dysfunction (BEAUTIfUL)trial, an ongoing large-scale, multi-center, placebo-controlled, random-ized trial.

REFERENCES

1. Gillman MW, Kannel WB, BelangerA, D’Agostino RB.

Influence of heart rate on mortality amongpersons with hypertension: the FraminghamStudy.

Am Heart J. 1993;125:1148-1154.

2. Palatini P, Casiglia E, Julius S,Pessina AC.

High heart rate: a risk factor for cardiovas-cular death in elderly men.

Arch Intern Med. 1999;159:585-592.

3. Tardif JC, Gregoire J, L’Allier PL,Joyal M.

Chronic heart rate reduction with ivabradineand prevention of atherosclerosis progressionassessed using intravascular ultrasound.


4. Diaz A, Bourassa MG, Guertin MC,Tardif JC.

Long-term prognostic value of resting heartrate in patients with suspected or provencoronary artery disease.

Eur Heart J. 2005;26:967-974.

5. Hjalmarson A, Gilpin EA, Kjekshus J,et al.

Influence of heart rate on mortality afteracute myocardial infarction.

Am J Cardiol. 1990;65:547-553.

6. Disegni E, Goldbourt U, Reicher-Reiss H, et al.

The predictive value of admission heart rateon mortality in patients with acute myocar-dial infarction. SPRINT Study Group. Secondary Prevention Reinfarction IsraeliNifedipine Trial.

J Clin Epidemiol. 1995;48:1197-1205.

7. Zuanetti G, Mantini L, Hernandez-Bernal F, et al.

Relevance of heart rate as a prognostic factorin patients with acute myocardial infarction:insights from the GISSI-2 study.

Eur Heart J. 1998;19(suppl F):F19-F26.

8. Kjekshus J.

Importance of heart rate in determiningbeta-blocker efficacy in acute and long-termmyocardial infarction intervention trials.

Am J Cardiol. 1986;57:43F-49F.

9. Borer JS, Fox K, Jaillon P, Lerebours G.

Antianginal and anti-ischemic effects ofivabradine, an If inhibitor, in stable angina:a randomized, double-blind, multicentered,placebo-controlled trial.

Circulation. 2003;107:817-823.

10. Tardif JC, Ford I, Tendera M,Bourassa MG, Fox K.

Efficacy of ivabradine, a new selective If

inhibitor, compared with atenolol in patientswith chronic stable angina.

Eur Heart J. 2005;26:2529-2536.

11. Colin P, Ghaleh B, Monnet X, et al.

Contributions of heart rate and contractilityto myocardial oxygen balance during exercise.

Am J Physiol Heart Circ Physiol.2003;284:H676-H682.

12. Simon L, Ghaleh B, Puybasset L,et al.

Coronary hemodynamic effects of S16257,a new bradycardic agent, in resting andexercising conscious dogs.

J Pharmacol Exp Ther. 1995;275:659-666.

13. Monnet X, Colin P, Ghaleh B,Hittinger L, Giudicelli JF, Berdeaux A.

Heart rate reduction during exercise-inducedmyocardial ischaemia and stunning.

Eur Heart J. 2004;25:579-586.

14. Persky A, Olsson G, Landou C,de Faire U, Theorell T, Hamsten A.

Minimum heart rate and coronaryatherosclerosis: independent relations toglobal severity and rate of progression of angiographic lesions in men with myocardial infarction at a young age.

Am Heart J. 1992;123:606-616.

15. Beere PA, Glagov S, Zarins CK.

Retarding effect of lowered heart rate oncoronary atherosclerosis.

Science. 1984;226:180-182.

16. Kaplan JR, Manuck SB, AdamsMR, Weingand KW, Clarkson TB.

Inhibition of coronary atherosclerosis bypropranolol in behaviorally predisposedmonkeys fed an atherogenic diet.

Circulation. 1987;76:1364-1372.

17. Strawn WB, Bondjers G, KaplanJR, et al.

Endothelial dysfunction in response to psychosocial stress in monkeys.

Circ Res. 1991;68:1270-1279.

18. Skantze HB, Kaplan J, PetterssonK, et al.

Psychosocial stress causes endothelial injuryin cynomolgus monkeys via beta1-adreno-ceptor activation.

Atherosclerosis. 1998;136:153-161.

19. Hedblad B, Wikstrand J, Janzon L,Wedel H, Berglund G.

Low-dose metoprolol CR/XL and fluvastatinslow progression of carotid intima-mediathickness. Main results from the beta-blockercholesterol-lowering asymptomatic plaquestudy (BCAPS).

Circulation. 2001;103:1721-1726.

20. Heidland UE, Strauer BE.

Left ventricular muscle mass and elevatedheart rate are associated with coronaryplaque disruption.

Circulation. 2001;104:1477-1482.



41


43

he woeful state of knowledge ofcongenital heart disease at thebeginning of the 20th centurycan be appreciated by examin-

ing two major textbooks. Osler’s ThePrinciples and Practice of Medicinedevotes 4 pages to this subject, whichis described as of

only limited clinical interest, as in a large

proportion of the cases the anomaly is not

compatible with life, and in others nothing

can be done to remedy the defect or even

to relieve the symptoms.1

Mackenzie’s Diseases of the Heart haseven less to say; a single page on “Con-genital Affection of the Heart” includesstatements such as

The most characteristic symptom is cyanosis,

which is present in a great number of pa-

tients. [and] Murmurs are usually present,

almost invariably systolic in time…2

Lack of interest in these conditionswas due in part to the fact that, withthe notable exception of patent ductusarteriosus that has a characteristic“machinery” murmur, virtually none ofthese conditions could be diagnosedin living patients. In 1931, Paul Whitewrote that the possibility of identify-ing a particular defect in a living pa-tient had

seemed so remote some years ago that a

diagnosis more detailed than that of “con-

genital heart disease” was considered fool-

hardy, and even this diagnosis was ventured

often with uncertainty.3

In 1944, commenting on the “greatprogress [that] has occurred in the pasttwelve years,” White acknowledged the“pioneer work of enthusiastic studentsof the subject, especially Maude Abbottof Montreal…”4 More recently, Aciernodescribed Abbott’s contribution as

a comprehensive, organized, and system-

atized knowledge of congenital heart dis-

ease, [which] provided insight into the

pathophysiologic pathways [that] enabled

surgeons to devise a rational surgical

method for correction or amelioration of

the altered physiology.5

MAUDE ELIZABETHABBOTT

Maude Abbott (Figure 1),5-7 the sec-ond daughter of the reverend JeremiaBabin and Elizabeth Abbott, was bornin March 1869, in a small village ineastern Quebec. Her father had desert-ed his family before Abbott was bornand her mother (like seven of her eightsiblings) died at a young age of tuber-culosis; as a result, Abbott was adopt-ed and raised from infancy by her ma-ternal grandmother. She was initiallyeducated at home by a governess, andfrom 1884 to 1886 attended a privateschool in Montreal. The diary she wroteas a child portrays a gentle, introspec-tive young woman with a strong desireto become educated at a time whenwomen’s access to a university educa-tion was severely limited. Thanks inpart to a recent gift to support highereducation for women, Abbott won ascholarship to McGill University, butbecause a smallpox epidemic in Mon-treal caused her grandmother to fearfor her safety, she did not begin herstudies until 1886. Four years later, hav-ing been class president every year andeditor of the college’s only publication,she graduated as valedictorian, havingearned the Lord Stanley Gold Medalfor academic excellence. Abbott ap-

Address for correspondence:Prof Arnold M. Katz, 1592 New Boston Road,PO Box 1048, Norwich VT, 05055-1048, USA(e-mail: [email protected])


T

Icons of CardiologyMaude Elizabeth Abbott:

bringing order to congenital malformations of the heartArnold M. Katz, MD

Professor of Medicine Emeritus - University of Connecticut School of Medicine Visiting Professor of Medicine and Physiology - Dartmouth Medical School - Dartmouth, Mass - USA

From the Cardiology Division - Department of Medicine - University of Connecticut Health Center - Farmington, Conn - USA

Figure 1. Maude Abbott, aged 25, at the time of her graduation from theMedical College of Bishop’s University.

Reproduced from reference 6:MacDermot HE. Maude Abbott.

A Memoir. Toronto, Canada: Macmillan;1941. Copyright © 1941, Macmillan.

pears to have decided on a career inmedicine during her second year incollege when a childhood friend askedabout her plans and she replied “if Iweren’t an artist I would be a doctor.It’s a lovely life. So human and full ofpeople.”6 This desire to help others wasapparent after Abbott graduated fromcollege, when she and other womengraduates worked in a soup kitchen forfactory and working girls.

Abbott applied to study medicine atMcGill, where she had strong familyties, but was met with an adamant re-fusal because she was a woman; theRegistrar wrote: “I am sorry to informyou that the Faculty of Medicine canhold out no hope of being able tocomply with your request.”6 This ledAbbott and a few other women to ini-tiate a campaign that drew the supportof several newspapers and leadingphysicians, but which eventually failed.In 1890, therefore, Abbott enrolled inthe Medical College of Bishop’s Univer-sity, a small school in Montreal. Whenshe attempted to attend the lecturesof the summer session of McGill Med-ical School, she was again rebuffed;as noted by the Registrar:

The Faculty…were almost unanimously op-

posed to allowing young ladies to attend the

course in the Medical building, even dur-

ing the summer session, because it would

be a dangerous precedent; inasmuch as the

Faculty have already declared themselves

opposed to co-education in medicine.6

The women medical students atBishop’s College were subsequentlytold they could not attend rounds onthe wards at the Montreal GeneralHospital, an independent entity whereteaching was supervised by McGillFaculty. Abbott and her fellow femalestudents fought this refusal and cre-ated such a storm that several Gover-nors of the hospital refused to paytheir subscriptions and a local news-paper mocked the “poor little menstudents [who needed to be protected]from the great big lady students.”6

As a result, Abbott received the “tick-et” needed to study on these wards.

In 1894, having won the senior anato-my prize and the Chancellor’s prize forthe best examination in her final sub-jects, Abbott graduated from Bishop’swith honors. She immediately went toEurope for further training, spending9 months attending clinical rounds andoperations in England, Germany, andSwitzerland, after which she reachedVienna where for 2 years she studiedmainly obstetrics and gynecology.She returned to Canada by way of theUnited Kingdom where she passed licensing examinations in Edinburgh,which allowed her to serve as a locumtenens at a women’s hospital in Glas-gow and as a clinical assistant at thecity asylum in Birmingham. She opened

a practice in Montreal in September1897, but made little mention of thisin her memoirs; a contemporary de-scribed Abbott at that time as “a fem-inine misfit in an exclusive male envi-ronment.”6

Abbott’s future opened in 1898, whenshe was appointed assistant curatorof the Medical Museum at McGill andbegan cataloguing a collection ofpathological specimens that dated backalmost 75 years. At this time Abbottcame under the influence of WilliamOsler, who for the next 20 years was toprovide both encouragement and guid-ance as she became the world’s author-ity on congenital heart disease. Herdemonstrations for the medical stu-dents at McGill received such highpraise that they became a required part


Maude Elizabeth Abbott: bringing order to congenital malformations of the heart - Katz

44

LALA RA

RA

Ventricle

Ventricle

A

B C

Right atrium

Rudimentarycavity

Aorta

Pulmonaryartery

Ventricle

Figure 2. Three examples of cor biatriatum triloculare (single ventricle). (A) The “HolmesHeart” (anterior view) from a 22-year-old man with cyanotic heart disease showing thesingle large ventricle with no septum and a rudimentary cavity that gives rise to thepulmonary artery. (B) Embryonic mammalian heart (cross-section) showing a singleventricle that receives blood from both the right atrium (RA) and left atrium (LA). (C) Adult turtle heart (dorsal view) whose single ventricle receives blood from both the rightatrium (RA, shown in outline as this structure was removed) and the left atrium (LA).

Modified from reference 9: Abbott ME. Atlas of Congenital Heart Disease. New York, NY:American Heart Association; 1936. Copyright © 1936, American Heart Association.

45

of the Pathology course. During andafter World War I, in addition to workat the Medical Museum, she brought amethod to measure basal metabolismthat she had learned in Boston toMontreal, gave a lecture on FlorenceNightingale at Harvard, was acting Ed-itor of the Canadian Medical Journal,and helped prepare (and pay for) amemorial to William Osler.7 HaroldSegall, a museum assistant who wenton to become one of Canada’s lead-ing cardiologists, described Abbott as having

about a dozen irons in the fire at the same

time, and all seemed in confusion. More-

over, she took on any new thing that came

up with the greatest of enthusiasm, indeed

as if she had nothing else to do. In her

demonstrations with students she would

speak rapidly, showing specimen after spec-

imen, with an enthusiasm which never fal-

tered. (Cited by reference 6.)

Abbott also began a catalog of thismuseum that Osler described as: “oneof the best pieces of work ever doneat the School… She evidently has agenius for this sort of thing.”8

CONTRIBUTIONS TO THE UNDERSTANDING

OF CONGENITAL HEART DISEASE

Abbott’s interest in congenital heartdisease appears to have been trig-gered by the “Holmes Heart,”a speci-men of cor biatriatum triloculare(single ventricle) in the McGill collec-tion that dated back to 1824 (Figure2A). Because this heart had been la-beled “ulcerative endocarditis,” whichwas obviously an error, Abbott wroteto Osler who had used this collectionwhen he taught at McGill; Osler repliedthat he remembered this specimen ashe had often shown it to students asa special form of a three-chamberedheart.6 Osler, impressed by Abbott’senergy and skills, asked her to write asection on congenital heart diseasefor his new System of Medicine. He

subsequently described Abbott’s sec-tion, the only one in his book writtenby a woman, as “…far and away thebest thing ever written on the subjectin English—possibly in any language.”(cited by reference 6). First publishedas a 22-page description of 412 hearts,Abbott’s section grew to 200 pages thatdescribed 1000 hearts6 and led to herAtlas of Congenital Heart Disease,9which provided a pathophysiologicaland statistical analysis of the clinicaland anatomical abnormalities in thesepatients.

In bringing order to what had previ-ously been a disorganized array offascinating, but poorly understood,congenital malformations of the heart,Abbott divided these patients intothree groups: Those with no abnormalcommunications, those with a left-to-right shunt (acyanotic), including pa-tients with shunt reversal later in life(cyanose tardive), and those with per-manent right-to-left shunt (cyanotic).9For each she developed a diagram ofthe circulation, one example of whichis depicted in a mural at the InstitutoNacional de Cardiologia in MexicoCity (Figure 3).10 Recognizing the im-portance of preventing these malfor-mations, Abbott developed 6 ques-tions to help elucidate their etiology(Table I). These questions, which todayare asked in terms such as genetic,

chromosomal, and developmentalmechanisms, provided an impetus forour modern understanding of the eti-ologies of congenital heart disease.

LATER LIFE

In 1910, after Abbott gained her repu-tation as an authority on congenitalheart disease, McGill awarded her anhonorary MD degree and, in additionto her title as Curator of the MedicalMuseum, she became Governor’s Fel-low in Pathology from 1905 to 1909and lecturer in pathology from 1910 to



Table I.

QUESTIONS PROPOSED BY ABBOTT TO HELP EXPLAINTHE ETIOLOGY OF CONGEN-

ITAL CARDIOVASCULAR MALFORMATIONS

1. Did the abnormality result froma fault in the germ plasm?

2. Was the abnormality inherited?

3. Did the abnormality occur be-cause of a change in the envi-ronment of the embryo in utero?

4. Was the abnormality a result ofmaternal disease?

5. Was the abnormality due to fetaltrauma or a uterine disorder?

6. Did a disease affecting the earlyembryo cause the abnormality?

Figure 3. Abbott, along withRokitansky and a deeply cyanoticchild as depicted in Diego Rivera’smural in the Instituto Nacionalde Cardiologia in Mexico City.Rivera’s image is clearly basedon the photograph shown asFigure 4.

Reproduced from reference 10:Diego Rivera. Sus Frescos en elInstituto Nacional de Cardiologiapor el Doctor Ignacio ChavezMiembro Fundador de “El Cole-gio Nacional.” Mexico City,Mexico: Sociedad Mexican deCardiología; 1946. Copyright ©1946, Sociedad Mexicana deCardiología.

1923. In 1923 she went to Philadelphiaas chair of the Pathology Departmentat the Women’s Medical College ofPennsylvania, but after a stay of 2 yearsduring which she significantly raisedthe status of this department, she re-turned to McGill where she remainedas assistant professor of medical re-search until her retirement in 1936.Her enthusiasm continued unabated,as evidenced by the following story,told by William C. Gibson who metAbbott in 1933 when he was a stu-dent:

One day a heavy grey haired wom-

an came into the library where I

was working, and recognizing [that

I was examining] the Osler note-

books, asked if I was an out-of-town

researcher in medical history. I

replied that I was a first year medical

student at McGill and was interested

in Osler. That was my fatal mistake! I was

at once whisked downstairs by this bustling

human dynamo who seemed only to cling

to the stair rail, letting her feet find the

steps if they could. Within a few minutes

I was seated in the midst of a sea of charts,

book, and pictures. (Cited by reference 6.)

This encounter began a five-year col-laboration on a new edition of theOsler Bibliography that continued whenGibson left Canada to study in Oxford,from where he pleaded that becauseof “the broad expanse of the AtlanticOcean” he would find it difficult to con-tinue working on this project. However,Abbott insisted, and when Gibson’swork on the bibliography hit a snag,Abbott wrote “as if she might comeover and scalp me as a low grade pro-crastinator.”6 Happily, the bibliographywas published in 1939.

Abbott retired in 1936 at the prescribedage of 67 with the remarkably inappro-priate rank of assistant professor ofmedical research, considering that inaddition to her many scholarly achieve-ments she was a Charter Member ofthe Royal College of Physicians ofCanada and a Fellow of the Royal So-

ciety of Medicine, London, England.Shortly after her retirement, however,McGill did award her a honorary LLD,the highest academic honor they couldconfer. She remained active, continu-ing to publish and lecture (Figure 4) 6

until July 1940 when she had a cere-bral hemorrhage; she died 2 monthslater, on September 2.

CONCLUSIONS

Maude Abbott is remembered todaylargely for her seminal work on congen-ital heart disease, which is describedin more than 40 of her 116 publica-tions,6 and her Atlas of CongenitalHeart Disease,9 which summarized hermajor academic contribution and pro-vided the foundation of our modernunderstanding of these malformations.However, her written work is only apart of her contribution to medicine.Those who knew Abbott place evengreater emphasis on her remarkablepersonal qualities, describing her asan energetic, enthusiastic woman whowas warm, unselfish, and completelynatural. MacDermot, whose biographycaptures her indomitable personality,wrote that even though Abbott was a

pioneer who clarified the once obscurefield of congenital heart disease, hercharacter was itself “a contribution, andone which was probably more impor-tant, if less tangible.”6 Paul White,whose 3rd Edition of Heart Disease 4

includes a foldout table showingAbbott’s classification, wrote:

…far more important than any of her writ-

ten works was her vital stimulus to other

workers. Her spirit was indefatigable… many

of the contributions… to our knowledge of

congenital heart disease made by others

are due directly to Maude Abbott’s in-

fluence… it is not simply as the world’s

authority on congenital heart disease

that Maude Abbott will be best re-

membered, but as a living force in the

medicine of her generation. Hers was

a great spirit. (Cited by reference 6.)

Abbott, who was born 10 yearsafter publication of Darwin’s Ori-

gin of the Species and 2 years beforehis Descent of Man, clearly docu-mented the practical importance ofhuman evolution by basing her analy-sis of congenital heart disease on themany similarities between the malfor-mations, the structure of embryonicmammalian hearts, and the architec-ture of reptilian hearts (Figure 2).She observed that

knowledge of the successive stages through

which the mammalian heart passes in its

evolution from its primitive tubular state

to the completely divided four-chambered

organ conducting a double circulation [al-

lows] the most bizarre combinations of de-

fects [to] be interpreted quite simply, as due

to early arrests of development, marked as

it may be by ingenious structural adapta-

tions of growth.9

In describing the importance of com-parative anatomy, she noted the “trulyextraordinary way in which [the] vari-ous orders in the ascending vertebratescale mirror the successive stagesthrough which the human heart pass-es in very early intrauterine life,”9 andhow this ontogeny presents “a com-plete review of this organ’s evolution

46



Figure 4. Abbott, aged 67, when on a lecture tour.

Modified from reference 6: MacDermot HE.Maude Abbott. A Memoir. Toronto, Canada:

Macmillan; 1941. Copyright © 1941, Macmillan.

down to the closure of the cardiacsepta in the eighth week of fetal life.”9

Abbott also highlighted the impor-tance of a detailed study of the individ-ual patient, as well as of large groups,when she observed:

It is… a well known fact that, in clinical

medicine, the intimate knowledge of a rel-

atively small number of individual cases is

likely to yield a richer harvest of understand-

ing of diseased conditions than wider gen-

eralizations covering a more vast material.9

REFERENCES

1. Osler W.

The Principles and Practice of Medicine.

New York, NY: Appleton; 1892.

2. Mackenzie J.

Diseases of the Heart.

London, UK: Oxford University Press; 1908.

3. White PD.

Heart Disease.

1st ed. New York, NY: Macmillan; 1931.

4. White PD.

Heart Disease.

3rd ed. New York, NY: Macmillan; 1944.

5. Acierno LJ.

The History of Cardiology.

London, UK: Parthenon; 1994.

6. MacDermot HE.

Maude Abbott. A Memoir.

Toronto, Canada: Macmillan; 1941.

7. Wiglesworth FW.

Maude E. Abbott.

Perspect Pediatr Pathol. 1984;8:291-294.

8. Cushing H.

The Life of Sir William Osler.

London, UK: Oxford University Press; 1940.

9. Abbott ME.

Atlas of Congenital Heart Disease.

New York, NY: American HeartAssociation; 1936.

10. Diego Rivera.

Sus Frescos en el Instituto Nacional deCardiologia por el Doctor Ignacio ChavezMiembro Fundador de “El ColegioNacional.”

Mexico City, Mexico: Sociedad Mexican deCardiología; 1946.

47



his paper constitutes a landmark in the studyof mechanisms underlying generation of sinoa-trial nodal (SAN) activity. Hitherto, membranepotential measurement had offered a meansof measuring SAN spontaneous activity; how-

ever, in order to understand the underlying basis for this,direct measurements of membrane currents were needed.This required the use of the "voltage-clamp" technique, amethodology that allows control of cellular transmembranepotential, and measurement of corresponding ion flow.

Cardiac tissue presents particular challenges in terms ofthe study of ionic currents. Electrical coupling betweenadjacent cardiac cells makes it difficult to control adequatelythe membrane potential of multicellular preparations usingthe voltage-clamp method. This is undesirable because alack of adequate spatial control of membrane potentialintroduces unwanted measurement errors. Ultimately, thisproblem was to be solved by the advent of single-cell prepa-rations and the use of the patch-clamp, but it was to besome time later than 1976 when this study was performed—at this time, single-cell cardiac preparations were not avail-able. However, having previously applied the "sucrose-gap"voltage-clamp technique with limited success, Noma andIrisawa considered the electrical "cable" properties of theSAN and reasoned that an adequate voltage-clamp mightbe possible if the size of the SAN tissue preparation forstudy were to be limited by ligation, and voltage-clampwere to be achieved using the two-microelectrode record-ing technique, in which one electrode is used to controlmembrane potential and one to record ionic current.

Much of this paper is devoted to the development and vali-dation of the rabbit ligated SAN strand preparation. A keycriterion for success here would be a preparation smallenough that a voltage measured in the preparation wouldbe distributed uniformly, with minimal decrementationaway from the application point. In order to demonstrateadequate voltage-clamp of the preparation, the authorsadded a third electrode to monitor voltage and showedminimal deviation between measurements made with thiselectrode and the voltage-controlling electrode. In a carefully

executed series of experiments, it was shown that mem-brane potential was not homogeneous in preparations withdimensions of 1.7�0.3 mm and 0.7�0.3 mm, but that at0.3�0.3 mm such inhomogeneity was minimal.

It is in the last three figures of the nine in this paper thatwe see the first SAN ionic current data from this prepara-tion. The transient inward current elicited on depolarizationhas a voltage dependence now known to be characteristicof L-type calcium current, while outward current "tails" ob-served following depolarization and outward rectificationof the current-voltage relationship at positive voltages in-volve delayed rectifier potassium channels. A low mem-brane conductance was observed between –60 and –20 mVand is now accepted to be important for SAN function asit means that comparatively small ionic currents can havesignificant effects on membrane potential over this voltagerange. Importantly, on hyperpolarization to negative mem-brane potentials, an inward current was observed thatshowed a clear time-dependent increase throughout thevoltage command. The profile of this current is now clearlyrecognizable as that of If, though at the time the basis forthe inward current changes during and following hyperpo-larization was “difficult to explain.” What is clear, however,is that many of the cellular electrophysiological propertiesof the SAN that were later to be studied in detail are visiblein this study, which played a major role in setting the scenefor subsequent investigations.

50


Summaries of Ten Seminal Papers - Hancox and James

Membrane currents in the rabbit sinoatrial node cell studied by the double microelectrode method

A. Noma, H. Irisawa

Pflugers Arch. 1976;364:45-52

T

263 US citizens are evacuated from Beirut to avoidbecoming entangled in the Lebanese civil war; East German swimmers break 14 world records

at their national championships; and six Palestinians hijack an Air France Airbus

in Greece, taking 250 passengers hostage

1976



51

odulation of the activity of the sinoatrialnode (SAN) underpins the autonomic reg-ulation of heart rate, and this paper pro-vides a wonderful early insight into themechanism(s) by which adrenaline modu-

lates SAN activity. Previous studies had shown that adrena-line increased the slow inward (ie, calcium) current in otherareas of the heart; it was possible that this might mediateor contribute to the effects of adrenaline on the SAN. Thesmall multicellular SAN preparation developed by Nomaand Irisawa (see preceding Summary) provided a means bywhich the effects of adrenaline on both spontaneous ac-tivity and ionic currents could be studied.

Possibly due to the concise Nature paper format or to a sty-listic choice of the authors, detailed methodological infor-mation is not included in this report, though it is clear thatthe small rabbit SAN preparation of Noma and Irisawa wasused together with a two-microelectrode voltage-clamp.Initial measurements were made in the absence and pres-ence of adrenaline of both membrane potential and of therate of change of voltage during SAN spontaneous activity.At a physiologically relevant concentration of 50 nM, adrena-line increased both action potential amplitude and upstrokevelocity. These effects were consistent with an increase inthe slow inward current, particularly because they were madein the presence of tetrodotoxin, which would have inhibitedany fast sodium current in the preparation. In addition toits effects on the action potential upstroke, adrenaline alsoproduced a slight hyperpolarization of the maximum dias-tolic potential (the most negative membrane potentialreached following action potential repolarization) and ac-celerated the rate of action potential repolarization. Thissuggested that both inward (depolarizing) and outward(repolarizing) conductances were modulated by adrenaline.

Voltage-clamp measurements provided a direct demonstra-tion that the transient inward current was increased byadrenaline (500 nM). Significantly, the outward potassiumcurrent (IK) observed in the same experiments was also in-creased, confirming the notion that adrenaline exerted dualeffects on inward and outward conductances. These obser-

vations raised the question as to how adrenaline acceleratesrate as, while an increase in the slow inward current mightaccelerate the latter part of the pacemaker depolarization,the authors reasoned that the concomitant increase in IK

might act to decelerate the pacemaker depolarization. Thisled to an examination of the effect of adrenaline (100 nM)on time- and voltage-dependent current activated by hyper-polarizing voltage-clamps—making this the first report ofthe importance of If in the adrenergic modulation of heartrate. A significant and reversible increase in If was observed,which would be expected to accelerate the pacemaker po-tential under membrane potential recording conditions.

The importance of this observation is clear: it constitutesthe first evidence that modulation of If contributes to thepositive chronotropic effects of adrenaline. This is a remark-able contribution in itself, but doubly so in the context thatat this time the nature of If was unclear. It was consideredpossible that deactivation of a potassium current called IK2,as opposed to a distinct inward conductance, could under-lie If. As the authors commented in discussing their findings,testing the identity of If under voltage-clamp was difficultat that time, as the small SAN preparation did not readilytolerate the large voltage excursions necessary to examinethe ionic basis of the current. Nevertheless, this studyconstitutes a pivotal step in identifying If as an importantmeans of modulating SAN activity. Added to this, it is aclearly written and very readable report, and this makes itsfindings accessible to the specialist and nonspecialist alike.

M

Bjorn Borg defeats Roscoe Tanner to win the Wimbledon men’s singles title;

Nicaraguan president Gen. Anastasio SomozaDebayle resigns and flees into exile in Miami;

and Marxist philosopher Herman Marcuse, writer of One-Dimensional Man and Eros

and Civilization, dies, aged 81

1979


H. F. Brown, D. DiFrancesco, S. J. Noble

Nature. 1979;280:235-236



Functional and morphological organization of the rabbit sinus node

W. K. Bleeker, A. J. Mackaay, M. Masson-Pevet, L. N. Bouman, A. E. Becker

Circ Res. 1980;46:11-22

n order to gain an integrated understanding of thegeneration and conduction of sinoatrial node (SAN)activity, two types of experimental data are required:first, those data that provide insight into the ionicbasis of impulse generation at the cellular level and,

second, those indicating how impulse propagation occursthrough the intact node and between this and adjacentatrial tissue. Morphological investigations before this studyhad shown the SAN to be a heterogeneous structure, butmorphology alone was insufficient to provide insight intothe location of the dominant pacemaker site within the SANor to predict how emerging excitation would spread. Thisstudy constitutes an important landmark, as it sought toboth map excitation within the node and to correlate thiswith structural properties of the SAN.

In the 25 years since this study, technical advances havebeen made in recording techniques such that nowadaysmultielectrode arrays or optical mapping with voltage-sen-sitive dyes offer ways of studying excitation spread at thetissue level. At the time of this study, however, such op-tions were not available. Instead, using a preparation fromthe rabbit heart comprising the SAN, intercaval region,and roof of the right atrial appendage, the authors of thisstudy employed single mircoelectrode recordings to mapexcitation within the SAN area. This is a painstaking andtechnically challenging approach: to produce an excitationmap, such recordings would both need to be relative to atime-reference value and to allow proximate recordings to be made with a high degree of spatial resolution. Thetime-reference was provided by an electrogram obtainedfrom a surface electrode placed on the inferior part of thecrista terminalis. A high spatial resolution in control ofposition was obtained by mounting the micromanipulatorcontrolling the microelectrode onto a mechanical stagewith lateral movements accurate to 0.01 mm. Initial meas-urements during each experiment located the area ofpreparations where electrical propagation was slowest.Then a series of 150 to 300 successive impalements waspainstakingly made over 3 to 5 hours over an area approx-imating 4�6 mm. The spatial resolution between impale-ments in the pacemaker region was 0.2 mm.

The site of earliest activation was found to lie within theintercaval region, between 0.5 and 2 mm from the medialborder of the crista terminalis. Excitation then propagatedpreferentially towards the crista terminalis in an obliquecranial direction, but was markedly slower in other direc-tions and was blocked toward the interatrial septum. Withinthe intercaval region, the SAN was identified by distinctstaining properties from atrial cells. Within the SAN region,distinct zones could be identified. The central compactnode was characterized by cells showing a compact, inter-weaving structure, while in the nodal periphery cells lay ina parallel fashion. The leading pacemaker site was locatedas a group of ≈5000 cells within the compact node. Centralnodal cells were smaller in size than those in the peripheryof the node. Electron microscopy showed gap junctions tobe present throughout the node, but to be larger and morefrequent towards the periphery. Unlike atrial muscle, wherethey were found preferentially at intercalated discs, thegap junctions were dispersed randomly at the cell surface.

This report set the scene for subsequent studies in a num-ber of respects: it laid the foundations for investigation of heterogeneity of cellular electrophysiology and also ofconnexin isoforms that underlie gap junctions within theSAN, for the development of models of SAN regional het-erogeneity (the mosaic and gradient models), through tothe present when 3-dimensional combined anatomical andfunctional SAN models lie within reach.

I

American writer Henry Miller, author of Tropic of Cancer and Tropic of Capricorn, dies, aged 87;

nuclear physicist Andrei Sakharov is sent into exile in Gorky after speaking out against

the Soviet presence in Afghanistan; andRobert Mugabe returns to Rhodesia (Zimbabwe)

after five years in exile

1980

52



rior to this study, the ability of acetylcholine(ACh) to increase potassium conductance ofpacemaker tissue had already been recognized.Indeed, fluctuation analysis had provided evi-dence that this effect resulted from activation of

a distinct potassium channel coupled to muscarinic AChreceptors (mACh-R) in the pacemaker cell membrane. Theimportance of this conductance was considered to be that,by decreasing nodal cell excitability, it would reduce therate of sinoatrial node (SAN) spontaneous activity andthereby heart rate. What had not been reported prior tothis study were direct measurements of single channelbehavior of the mACh-R–activated conductance.

Today, a key difference between pacemaker and nonpace-maker tissues is considered to be a strong role for an in-wardly rectifying K+-current called IK1 in setting the restingpotential of ventricular and atrial cells; in pacemaker tis-sues, IK1 channels are sparse or absent. Importantly, thisstudy showed that the ACh-activated K+ current in pace-maker cells is mediated by a distinct channel, which wasto be reinforced later when the molecular basis of thechannel was also found to be distinct from that of otherinwardly rectifying K+ currents in the heart.

Two key technical advances made this investigation possi-ble. First, enzymatic and mechanical dispersion methodshad been developed to allow the isolation of single cardiaccells for electrophysiological study. Second, the develop-ment of the patch-clamp technique allowed recordings fromsmall areas of cell membrane. In this, the application ofsuction to low-resistance glass pipettes placed against thecell membrane forms a high-resistance seal, and currentflow in response to voltage changes across the small“patch” of membrane occurs through any ion channels inthis area of the membrane. Channel openings in suchrecordings are visible as rectangular deflections duringwhich tiny currents (in the order of 10–12 A) flow. The im-pact of this technique on increasing understanding of ionchannel function cannot be overstated: it’s developers(one of whom is the first author of this study) were later(1991) to win the Nobel Prize for Physiology or Medicine.

The experiments in this paper were performed on singlecells isolated from both the SAN and the atrioventricularnode (AVN). Initial measurements were made of ACh-acti-vated current at the whole-cell level; this was larger at nega-tive than at positive voltages (a property termed "inwardrectification") and depended on the external K+ concentra-tion as expected for a K+ current. Single channel measure-ments were then made, and by changing the voltage acrossthe patch the authors obtained single channel conductancevalues for the ACh-activated current: this was greater atnegative than at positive voltages, consistent with the in-wardly rectifying nature of the whole-cell current. Singlechannel currents were strongly K+-dependent and also de-pendent on the ACh concentration applied.

Cells that responded to ACh showed a second interestingfeature: in the absence of ACh, they exhibited spontaneouschannel openings of similar size and duration as the ACh-activated current, but at a lower frequency. It was conclud-ed that this resting K+ channel activity could representspontaneous openings of the ACh-activated channels. Innodal cells without spontaneous activity, and in atrial cells,a distinct type of resting K+ channel (with much longerchannel openings, resembling the resting K+ channels ofventricular cells) was visible, suggesting that resting K+

channel activity differed between pacemaker and nonpace-maker cells. The study concludes with a study of the gatingbehavior of the ACh-activated channel current based on atwo-step reaction underlying channel activation.

P

Konrad Kuja, a calligrapher from Stuttgart, admits to faking the Hitler diaries; the Iranian

Communist Tudeh party is dissolved; andthe South African air force bombs ANC bases in Maputo in retaliation for a car bombing in

Pretoria that killed 18 and injured 190

1983

Acetylcholine activation of single muscarinic K+ channels in isolated pacemaker cells of the mammalian heart

B. Sakmann, A. Noma, W. Trautwein

Nature. 1983;303:2506253

53



54

hy doesn’t atherosclerosis affect all humanarteries equally? This is an importantquestion as areas around arterial branchpoints and curves are particularly suscep-tible, and the coronary arteries, the ab-

dominal aortic segment, carotid bifurcation, and vesselssupplying lower extremities tend to be affected in a muchworse way by atherosclerosis than do other major arteries.

While an intuitively obvious answer might be that high shearstress predisposes toward plaque formation, in fact theevidence at the time of this study by Beere and colleagueswas that, in the case of the carotid bifurcation, it is lowshear stress and oscillations in shear stress direction (whichoccur during pulsatile flow) that are the major hemody-namic risk factors associated with lesion formation.

Coronary arteries are particularly predisposed towards se-vere atherosclerosis, with plaque formation tending to localize at branch points. Coronary arterial blood flow un-dergoes several alterations during each cardiac cycle: duringthe isovolumetric contraction and rapid ejection phasesof systole it decreases; it increases as peak systolic aorticpressure exceeds intracoronary pressure, then decreasesduring the remainder of systole. During isovolumetric relax-ation in diastole, coronary flow is greatest, while it gradu-ally decreases during ventricular filling. The authors of thisstudy reasoned that if hemodynamic changes are importantto coronary arterial plaque formation, a high heart rateshould exacerbate coronary atherogenesis, while a low ratemight have a protective effect.

This idea was investigated using surgical ablation of thesinoatrial node (SAN) in cynomolgus monkeys (a speciesof macaque originally from South-East Asia), with a shamprocedure being carried out as a control and an additionalgroup that did not undergo surgery. An atherogenic diet(incorporating 25 % peanut oil and 2% cholesterol) wasgiven to each group for 6 months and heart rate was moni-tored routinely by telemetry. When atherosclerotic lesionarea and average and maximum stenosis were subsequentlycompared between control and SAN ablation groups, there

was no significant difference. However, when animals thathad undergone surgery were grouped according to whetherheart rate was less than or greater than the preoperativemean (classified as "low heart rate" and "high heart rate"groups, respectively), the values of these indicators ofcoronary atherosclerosis in the high heart rate group weregreater (by more than twofold) than those from the lowheart rate group. Comparisons of blood pressure, weight,and cholesterol and triglyceride levels showed no differ-ences in these between low and high heart rate groups.Therefore, heart rate itself appeared to be influencing theseverity of atherosclerotic lesions.

Since this study, the association between a high heart rateand atherosclerotic plaque formation has been reinforced,while a high rate has also been associated with increasedcoronary plaque disruption. What then are the implicationsof such associations? First, regular aerobic physical activityis associated both with a reduction in resting rate in hu-mans and with a protective effect against coronary arterydisease. Second, regular stress-induced heart rate risesduring either prolonged psychological stress or in associa-tion with “Type A” personality traits would be anticipatedto elevate resting rate for prolonged periods and, in turn,this might link to coronary atherogenesis. Third, if an ele-vated resting heart rate is an independent risk factor forcoronary atherosclerosis, then heart rate reduction shouldbe expected to reduce the rate of lesion development inat-risk groups. Results that emerged from the BCAPS (β-Blocker Cholesterol-lowering Asymptomatic PlaqueStudy) trial in 2001 are consistent with this notion.

W

Retarding effect of lowered heart rate on coronary atherosclerosis

P. A. Beere, S. Glagov, C. K. Zarins

Science. 1984;226:180-182

Indian Prime Minister Indira Gandhi is assassinatedby two members of her personal bodyguard;

China announces a program of economic reformsgiving factory owners greater autonomy; and

Italy indicts three Bulgarians and four Turks in the conspiracy to assassinate the Pope

1984



uth et al performed this study against a back-ground in which, while a number of drugswere known to be beneficial in treating effort-induced angina pectoris, precise mechanismsunderlying the beneficial effects had not been

established. Cardioselective β-blockade might be expectedto have a number of effects that would mitigate the effectsof restricted blood flow in local ischemia. For example, in asetting of restricted coronary inflow, lowering of heart ratewould increase time for tissue perfusion during diastole.Also, the negative inotropic effect of β-adrenoceptor block-ade would reduce the oxygen demand of nonischemic tissueand possibly also any discrepancy between oxygen supplyand demand of such tissue. A reduction in left ventricularpressure consequent upon β-blockade could also contributeto improved function in the ischemic region. However, whilethis range of possibilities was appreciated, the relative im-portance of heart rate reduction compared with other con-sequences of β-adrenoceptor blockade was not known.

The authors addressed this question using a canine modelin which regional ischemia and dysfunction were inducedby using an aneroid constrictor to produce coronary steno-sis of the left circumflex artery. Following recovery fromsurgery, regional ischemia was induced in conscious dogsby treadmill exercise. Blood flow and ventricular wall dys-function were assessed under differing conditions: a con-trol run (no treatment), following administration of the β-adrenoceptor blocker atenolol, and in the presence ofatenolol, but with atrial pacing to prevent the reduction ofheart rate. This neat experimental design allowed the au-thors to determine, at a matched workload, the relative im-portance of heart rate reduction in the overall effects ofatenolol.

The results are striking. In the absence of atenolol, wallthickening of the ischemic zone during systole was some-what compromised, but atenolol administration improvedthis (nearly doubling the measured value) along with pro-ducing the expected reduction in heart rate. However, whenthe negative chronotropic effect of atenolol was preventedby pacing, no improvement of wall thickening during systole

in the ischemic zone was seen, rather this fell to a value thatwas lower than that in the absence of atenolol, possiblybecause β-blockade may have unmasked α-adrenergicvasoconstriction in the ischemic myocardium.

Eliminating the heart rate reduction produced by atenololwould not have removed its other possible beneficial ac-tions—for example, the potential metabolic benefits ofpreventing the inotropic effect of increased sympatheticdrive during exercise. So the inference that can be drawn isthat heart reduction per se was the key player in the ben-eficial effect of β-blockade, likely by increasing diastolicperfusion time, resulting in improved diastolic flow to theischemic myocardium. A link here to If is not hard to see:β-adrenoceptor blockade would be expected to prevent/limitaugmentation of If resulting from increased sympatheticdrive (see Summary of paper by Brown et al, page 51 ),with a consequent limitation on heart rate increase.

The results of this study also set the scene for the investi-gation of other means of heart rate reduction. Indeed, theauthors suggest that specific bradycardic agents could bebeneficial for exercise-induced ischemia, producing heartrate reduction without the negative-inotropy (or indeedthe range of side-effects) of β-adrenoceptor blockade. Sincethat time, specific If inhibition has been seen to produceheart rate reduction without limiting beneficial stroke vol-ume changes, with positive effects in terms of angina pre-vention, and with minimal side effects—the main onesbeing transient and reversible visual disturbances due tothe role of an If -like current in visual transduction.

G

Mechanism of beneficial effect of beta-adrenergic blockade onexercise-induced myocardial ischemia in conscious dogs

B. D. Guth, G. Heusch, R. Seitelberger, J. Ross Jr

Circ Res. 1987;60:738-746

55

Iraqi missiles kill 37 in an attack on the US frigate Stark in the Persian Gulf;

the trial of nazi war criminal Klaus Barbie opens in Lyon; and US film actress Rita Hayworthdies after a long battle with Alzheimer’s disease

1987



56

y the time this study was conducted, it wasknown that acetylcholine (ACh) could modulatemultiple ionic currents: activation of a K+ con-ductance (IKACh, see summary of paper by Sak-mann et al, page 53 ), reduction of the slow in-

ward current (Isi), and inhibition of If had all been reported.However, the question arose as to whether activation ofIKACh or inhibition of If is the predominant mediator of thenegative chronotropic effect of ACh at physiologically rel-evant concentrations. Therefore, this study was performedin order to make a direct comparison of the effects of AChon If and IKACh, using the rabbit isolated sinoatrial node(SAN) cell preparation and whole-cell patch clamp tech-nique. The key here was that by studying both currents ina single study, it would be possible to determine the rela-tive potency of ACh effects on the two currents in a morereliable fashion than would be possible by comparing datafrom different investigations.

In the first experiments shown, the authors observed thatinhibition of If occurred at ACh concentrations an order ofmagnitude lower than that necessary for IKACh activation.Precise quantification of the difference was not possible inthese initial experiments in which both currents were stud-ied concomitantly, because at higher concentrations effectson the two currents overlapped. Therefore, the authorsproceeded to quantify the difference by studying each cur-rent under selective recording conditions. Barium ionsblock IKACh, so selective If measurements were made withBa2+ present, while IKACh was measured in a voltage rangeat which If channels would not have been active. For inhi-bition of If, the half-maximal ACh concentration was foundto be 13 nM, while that for activation of IKACh was 260 nM.Thus, there was a 20-fold difference in the potency of thetwo effects of ACh. A limited number of measurements ofeffects of ACh on Isi were performed, in which a low (10 nM)ACh concentration failed to alter Isi, whereas at higherconcentrations (100 nM and 1 µM) Isi was inhibited. Thus,under the conditions of this study, the predominant effectof low ACh concentrations was to attenuate If. When spon-taneous activity was measured, the majority of the slowingof action potential rate with ACh occurred below 100 nM,

consistent with a dominant role for If in mediating ACh’snegative chronotropic effect. A role for IKACh was not pre-cluded, but this was considered to play a role at high AChconcentrations. A similar argument applied to Isi.

The study is an elegant one and the message of the paperis clear: If is likely to mediate the negative chronotropiceffect of ACh at low concentrations, with two major mecha-nisms (If inhibition+IKACh activation) likely responsible athigher concentrations. So, is that it—job done—in termsof understanding vagal control of SAN rate? Well, not quite.This study sparked further investigation of the relative rolesfor If and IKACh with Boyett and colleagues studying bothsmall multicellular and single cell SAN preparations andpresenting evidence in 1995 for a dominant role for IKACh

over If in mediating the effect of ACh. This exemplifies thefact that, over the years, the pacemaking field has beendogged with conflicting experimental findings, leading tocontroversy as to the relative importance of If and other cur-rents in mediating particular aspects of control of SAN rate.

B

Muscarinic modulation of cardiac rate at low acetylcholine concentrations

D. DiFrancesco, P. Ducouret, R. B. Robinson

Science. 1989;243:669-671

Iran’s Ayatollah Khomeini declares author Salman Rushdie’s book The Satanic Verses

offensive, and sentences him to death; the last Soviet troops leave Afghanistan,

bringing and end to the 9-year war; and Czech playwright Vaclav Havel is jailed

for dissident activities

1989



57

Molecular characterization of the hyperpolarization-activatedcation channel in rabbit heart sinoatrial node

T. M. Ishii, M. Takano, L. H. Xie, A. Noma, H. Ohmori

J Biol Chem. 1999;274:12835-12839

lthough, historically, the patch-clamp tech-nique was pivotal in establishing the ionchannel concept, few would argue againstthe view that the development of molecularcloning techniques was the next technical

advance to revolutionize the study of ion channel function.This enabled genes responsible for ion channel proteins to be identified, it led to the ability to determine ionchannel gene mutations associated with ion-channel relat-ed diseases ("channelopathies") and, by targeting muta-tions to particular parts of ion channel proteins, it becamepossible to relate ion channel structure to function.

This paper identified a molecular candidate for the cardiacIf channel protein. In the lead-up to this study, three full-length and one partial cDNA clones encoding If-like chan-nels had been found in mouse brain, with a further cloneobtained from the sea-urchin testis. However, the molecu-lar identity of channels responsible for If in the heart wasnot clear.

Visiting the paper 6 years after its publication prompts adigression into ion channel nomenclature, for without thissome of the terminology used may seem a little confusing.As for some other ion channel genes, those responsiblefor channels carrying If-like currents have been given morethan one name. In the case of If, this was probably alwayson the cards, as even before candidate genes had beenidentified, the current had several names, being variouslylabeled If (funny current), IH (hyperpolarization-activatedcurrent), or simply pacemaker current.

Nowadays, the family of channels of which cardiac If is amember is generally known as the “hyperpolarization-acti-vated cyclic nucleotide-gated cation channel” (HCN chan-nel) family and the four genes that have been identified in mammalian tissues are termed HCN1-4. This paper usesan alternative terminology, with HAC (hyperpolarization-activated channel) in place of HCN. In turn, the membersof the HAC family isolated from mouse brain correspondedto cyclic nucleotide-gated (CNG) channels, and so one alsofinds the term BCNG (Brain-CNG) used in the text.

By screening a rabbit sinoatrial node (SAN) cDNA library,the authors identified a cDNA encoding a protein of 1150amino acids that showed a high degree of homology in thetransmembrane region to the previously identified mousepartial clone, BCNG-3. They named the SAN clone HAC4(now HCN4) and studied the distribution of its messengerRNA. This showed that HCN4 was most highly expressedin the SAN over other cardiac regions and that it was notsignificantly expressed in cerebellum, forebrain, kidney, orskeletal muscle. By expressing the HCN4 gene product in amammalian cell line, the authors found that HCN4 chan-nels exhibited characteristics concordant with those of If:time-dependent activation on membrane hyperpolarization,sensitivity to cyclic-AMP (a positive shift in voltage-depend-ent activation, as had been seen previously for If), sensitivityto block by Cs+ ions, and Na/K ion permeation properties.

The findings of this study have pretty much withstood thetest of time. HCN1 and HCN4 have been shown to be ableto form heteromeric channels in vitro and the rabbit SANhas been shown also to express message for HCN1 andHCN2, but that for HCN4 is by some margin the most abun-dant, implicating it as at least a key component if not thesole basis of SAN If. Identification of the HCN4 clone hasalso enabled its distribution throughout the SAN to bemapped and, as we shall see in the summary of the paperby Stieber et al (next page), it has also led to the targetedknockout of HCN4 in order to investigate the effect of itsabsence on native If and control of heart rate.

A

Students Eric Harris and Dylan Klebold stormColumbine High School, killing 12 other students,

a teacher, and then themselves; Libya hands over two suspects wanted for

the 1988 Pan Am jet bombing; andthe new Inuit territory of Nunavut officially

joins the Canadian Federation

1999

58



t is one thing to demonstrate the presence of an ionchannel candidate in a particular tissue type, but itis quite another to elucidate its contribution to thattissue’s functional activity. Selective pharmacologyoffers one possible approach, but is of limited value

when several channel isoforms exist, as in the case of theHCN family, but isoform-selective blocking agents do not.

A more elegant strategy is to eliminate expression of thechannel isoform of interest, either in isolated cells or intissues, by using antisense oligonucleotides, or short in-terfering RNA, or in the intact animal by the generation ofknockout mice. None of these approaches is without po-tential problems: cell or tissue culture can change electro-physiological properties, whereas targeted gene knockoutcan result in compensatory changes to other genes andalso relies on the suitability of the mouse for the questionto be investigated. However, despite such caveats, geneknockdown strategies are currently the best means avail-able of eliminating particular ion channel isoforms.

This paper builds upon accumulating evidence for HCN4being the predominant HCN isoform both in the adultsinoatrial node and in mouse embryonic hearts. The au-thors generated HCN4 knockouts, as well as animals withcardiomyocyte-specific deletion of HCN4. The first conse-quence of this was that both global and cardiomyocyte-specific HCN4 deletion resulted in animals that died be-tween embryonic days 9.5 and 11.5, in the absence of anycardiac structural abnormalities. Consequently, the datacome from embryonic, rather than adult, hearts and cells.

Homozygote knockout (HCN4 –/–), but not heterozygote(HCN4 +/–) embryonic hearts showed a significantly re-duced spontaneous contraction rate compared to wild-type(WT) hearts. HCN4 –/– hearts also showed a reduced sen-sitivity to pharmacological If blockade, suggesting that thebulk of drug-sensitive If was carried by HCN4. However, thefact that If inhibitors still exerted some bradycardic effecton HCN4 –/– heart beating indicates that HCN4 was not ex-clusively responsible for If. Moreover, the fact that –/– heartstreated with If blocker could still beat spontaneously sug-

gests that some pacemaking was possible independent ofIf, albeit at a markedly reduced rate. Electrophysiologicalinvestigation of cardiomyocytes from mutant embryosshowed a 70% to 90% attenuation of If, and cAMP applica-tion failed to alter heart beating rate or If activation. Thesedata all point toward a dominant (albeit not exclusive) rolefor HCN4 in mediating If and to a pivotal role for HCN4 inmediating the chronotropic effect of cAMP.

The skeptic might point out that in contrast to the adultheart, in the embryonic heart spontaneous activity is wide-spread and that the cardiomyocytes used for single cellelectrophysiology in this study could not be described assinoatrial. This study attempts to address this potentialproblem in two ways. First, the distribution of HCN4 washighly localized to a specific area of the developing heartthat is likely ultimately to develop into the adult sinoatrialnode. Second, the authors identified 4 distinct action po-tential profiles from embryonic cardiomyocytes, including“mature pacemaker-like action potentials.” These werepresent in a small proportion of WT embryonic cardiomyo-cytes, but were completely absent in those from HCN4 –/–

hearts. Considered collectively, therefore, the findings ofthis study provide compelling evidence that significant attenuation of If prevents normal development of normalembryonic cardiac activity and implicates HCN4 as a ma-jor player in this.

I

The hyperpolarization-activated channel HCN4 is required for thegeneration of pacemaker action potentials in the embryonic heart

J. Stieber, S. Herrmann, S. Feil, J. Loster, R. Feil, M. Biel, F. Hofmann, A. Ludwig

Proc Natl Acad Sci U S A. 2003;1000:15235-15240

American troops find Saddam Hussein in hidingnear Tikrit, who surrenders without a fight;

Muammar Qaddafi announces that Libya will giveup its nuclear, biological, and chemical weaponsprograms; and the Nobel Prize for Physiology orMedicine goes to Paul Lauterbur and Sir Peter

Mansfield for their discoveries leading to magnetic resonance imaging

2003

erhaps it is fitting to save the most recent studyselected for comment until last. A number ofepidemiological studies in the literature nowpoint toward the significance of a high restingheart rate in humans, with recognized associa-

tions between resting heart rate and mortality in patientswith hypertension, metabolic syndrome, and in elderly sub-jects. The importance of heart rate reduction in preventingangina is also now well recognized. However, until this re-port from Diaz and colleagues, there had been little infor-mation available regarding the prognostic value of restingheart rate in the setting of coronary artery disease (CAD).

This study, focusing on subjects with stable CAD, wasmade possible by the existence of the Coronary Artery Sur-gery Study (CASS), a multicenter program involving a largeregistry of patients who underwent coronary angiographyfor investigation of suspected or proven CAD and subse-quent medical or surgical treatment. The total pool of patients was large (24 959, consisting of 18 894 men and6065 women) and of these 24 913 were included in thisstudy, with a median follow-up time close to 15 years. Foranalysis, resting heart rate was divided into quintiles withthe top and bottom quintiles being ≤62 beats/min and≥83 beats/min, respectively. Patients in the top heart ratequintile were found to be at significantly greater risk forboth all-cause mortality and cardiovascular mortality (haz-ard ratio [HR], 1.32 and 1.31, respectively) than those inthe bottom quintile. Furthermore, high resting heart ratewas found to have a significant association with cardio-vascular rehospitalization.

What is particularly notable is that the prognostic value ofhigh heart rate for mortality was maintained when otherrisk factors/variables were taken into account (hypertension,diabetes, smoking, number of diseased coronary vessels,ejection fraction, recreational activity, body mass index[BMI]—in the case of cardiovascular mortality—and treat-ment with antiplatelets, diuretics, β-blockers, and lipid-low-ering drugs). It is also noteworthy that in this study thepredictive relationship between heart rate and mortalitywas similar for men and women. With such a large cohort,

it is reasonable to conclude, therefore, that in CAD patientsa high resting heart rate is an independent risk factor forboth cardiovascular and overall mortality.

If an abnormally high resting heart rate merits treatment tobring the rate into an acceptable range, the question arisesas to where the upper limit for a normal resting heart raterange stops and the lower limit of "too high" starts? Ofcourse, this question presupposes the existence of such acutoff as opposed to a continuum of risk. However, fromthe cutoff value used for the top quintile by Diaz and col-leagues, 83 beats/min would clearly appear too high, andPalatini, in an excellent editorial accompanying the paper(pages 943-945 of the same journal), comments that thisis concordant with previous results found in different clin-ical settings and suggests that resting values >80-85 beats/min should be considered abnormal.

It is too early to label this study a "classic," but it surely hasthe potential to become that. The ability to make treatmentdecisions based on accurate risk assessment is clearly ofparamount importance, and this study provides compellingevidence that in stable CAD, resting heart rate, which is astraightforward and inexpensive variable to measure, haspowerful predictive value and should therefore not beoverlooked.

P

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Long-term prognostic value of resting heart rate in patients withsuspected or proven coronary artery disease

A. Diaz, M. G. Bourassa, M. C. Guertin, J. C. Tardif

Eur Heart J. 2005;26:967-974

Mark Felt, a former top FBI official, admits to having leaked information to the Washington Post

about the 1972 Watergate break-in; Russian billionaire Mikhail Khodorkowsky, founder of the

Yukos oil company, is sentenced to 9 years inprison for fraud, embezzlement, and tax evasion;and French Prime Minister Jean-Pierre Raffarin

steps down days after voters reject a new constitution for Europe in a referendum

2005


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*Cardiovascular Division - King’s College - London - UK†Gustavus A. Pfeiffer Professor of Pharmacology - Columbia University - New York, NY - USA

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What If?


62


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