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Science, medicine, and the future
New pacing technologies for heart failure
Anthony W C Chow, Rebecca E Lane, Martin R Cowie
Heart failure is a sizeable problem in elderly populations, and although pharmacological treatmenthas improved, outcome generally remains poor. New pacing technologies have been developed totreat heart failure, with promising results The prevalence of heart failure in the general popula- tion is estimated to be 1-2% and increases rapidly with Summary box
age.1 In developed countries heart failure is a leading cause of admission to hospital among elderly patients New pacing technologies may now be used to and accounts for 1-2% of healthcare expenditure.2 treat selected patients with heart failure Although several pharmacological treatments have improved outcome,3–5 the prognosis of patients with Atrio-biventricular pacing has been shown to pharmacological approaches including cardiac trans- hospital in patients with left bundle branch block plantation have been limited by availability of organs, and the use of artificial left ventricular assist devices The results of randomised trials powered to test Recently, several promising new developments mortality benefits from biventricular pacing will have taken place in pacing technology to treat selected patients with heart failure. These include atrio- biventricular pacing to correct abnormal patterns of Implantable defibrillators reduce mortality in left ventricular contraction and implantable cardiac survivors of sudden cardiac death and patients defibrillators for treatment of malignant ventricular with ventricular arrhythcardiac and poor left arrhythmias. As the scale of the problem becomes ventricular function; recent clinical trials show apparent new treatments that have been shown to that indications for the use of these devices will be improve morbidity and possibly mortality in patients with chronic heart failure will undoubtedly have a major impact on clinical practice and healthcare The use of combined implantable defibrillators and atrio-biventricular pacemakers for patientswith heart failure is likely to increase—clear indications for such devices are beginning toemerge Sources and search criteria
We systematically searched PubMed for publications
on chronic heart failure and biventricular pacing,
in these patients.7 The prognosis for people with heart cardiac resynchronisation, and implantable cardio- failure remains poor. In clinical trials, death is most verter defibrillators for the years 1985-2003.
commonly due to either malignant ventriculartachyarrhythmias or progressive pump failure. Popula- The heart failure population
tion based studies report a mortality of close to 40% In the developed world the underlying cardiac within one year of diagnosis and around 10% per year abnormality for most patients with heart failure is thereafter.7 For patients who remain symptomatic at impaired left ventricular systolic function due to rest despite maximal medical treatment annual ischaemic heart disease or idiopathic dilated cardiomy- opathy.6 Despite maximal drug treatment manypatients still experience symptoms on minimal Ventricular dyssynchrony
exertion or even at rest (New York Heart Association An estimated 30% of patients with chronic heart fail- class III-IV), and this functional limitation often has a ure have evidence of abnormal interventricular marked impact on their quality of life. Recurrent and conduction on the 12 lead electrocardiogram, most prolonged hospital admissions for periods of decom- often in the form of left bundle branch block. The pensation of the heart failure syndrome are common resultant abnormal activation of the myocardium BMJ VOLUME 326 17 MAY 2003
activation. With a greater understanding of the conse-quences of deranged ventricular conduction came theproposal of using more sophisticated pacing configu-rations in an attempt to correct or normalise electricalactivation and improve cardiac performance. This hasevolved to form the basis of the concepts for cardiacresynchronisation.
Cardiac resynchronisation
Cardiac resynchronisation or biventricular pacing
entails inserting pacing leads via the cephalic or
subclavian veins into the right atrium and right ventri-
cle, as in conventional dual chamber permanent
pacing. In addition, however, a third pacing lead is
used to pace the left ventricle. In early studies this was
achieved by performing a thoracoscopic procedure
with placement of the electrode on the epicardial left
ventricular free wall.11 12 This necessitated general
anaesthesia and therefore carried appreciable risk in a
Fig 1 The anterior walls of the right atrium and ventricle have been
removed to show the lead arrangements used in biventricular pacing.
high risk group of patients. In 1998 Daubert et al pub- Tributaries that drain the left ventricle form the coronary sinus, lished the results of a study of a fully transvenous per- which opens posteriorly into the right atrium. The left ventricular manent biventricular pacing system,13 which revolu- lead shown is positioned in the antero-lateral cardiac vein, with tionised the technique (fig 1). Specially designed conventional pacing leads in the right atrial appendage and rightventricular apex (RA=right atrium; RV=right ventricle; LV=left catheters are inserted through the subclavian vein and ventricle). Used with permission from the authors (AWCC) passed down into the right atrium, from where the leftventricular coronary venous circulation can beaccessed. The coronary venous system consists of a causes deranged ventricular contraction or dyssyn- series of tributaries overlying the ventricular myocar- chrony, with regions of early and late contraction.
dium. They drain into the coronary sinus that opens Typically, the interventricular septum contracts early into the right atrium. This network of coronary venous relative to the delayed contraction of the lateral free branches can be visualised by performing a coronary wall of the left ventricle. In its most severe form sinus venogram (fig 2) and used to guide the dyssynchrony can result in contraction of the septum placement of the left ventricular pacing lead. The while the lateral wall is relaxing and vice versa. If three pacing electrodes are then connected to the opposing ventricular walls fail to contract together, a artificial pacemaker to allow biventricular pacing sizeable proportion of blood is simply shifted in the ventricular cavity instead of being ejected into thecirculation, thereby reducing cardiac output. The pro- Effects of biventricular pacing
portion of the cardiac cycle available for left ventricu- Biventricular pacing aims to restore synchronous lar filling and ejection is reduced by dyssynchronous cardiac contraction. Studies have shown that when contraction, which further contributes to a decrease in ventricular dyssynchrony is reduced the heart is able to the pumping ability of the heart. Even in structurally contract more efficiently and increase left ventricular normal hearts the presence of left bundle branchblock impairs cardiac ejection fraction. In patientswith chronic heart failure and poor systolic functionventricular dyssynchrony further compromises car-diac performance and may exacerbate symptoms ofheart failure.
Pacing for the treatment of heart failure
Permanent pacing has been used for many years to
treat symptomatic bradycardia and may alleviate heart
failure when associated with heart block. Several stud-
ies have examined the use of conventional dual cham-
ber atrio-right ventricular pacing for the treatment of
heart failure, in the absence of symptomatic bradycar-
dia or heart block, in an attempt to enhance cardiac
performance, but results have been inconsistent.9 10 In
most studies, right ventricular pacing produced no
haemodynamic benefit or had detrimental effects on
left ventricular function. This probably reflects the fact
that right ventricular apical pacing (which creates a
left bundle branch block pattern) induces ventricular
dyssynchrony, with detrimental effects on overall
Fig 2 Coronary sinus venogram taken with a veno-occlusive balloon
pump function of the heart. Many centres now (V) inflated. Left ventricular tributaries from the great cardiac vein advocate pacing from the right ventricular septum to and a lateral cardiac vein are shown draining into the coronary sinus.
provide a more physiological pattern of ventricular Used with permission from the authors (AWCC) BMJ VOLUME 326 17 MAY 2003
reduced by 50% in the group receiving biventricularpacing, and a staggering 77% reduction of total hospi-tal days saved for treating heart failure was observed inthe paced group compared with the control group. Asthe clinical trial lasted only six months it is still uncer-tain whether the benefits of biventricular pacing will besustained or increased with a longer period of followup. Thus the benefits seen with biventricular pacing notonly seem to improve the quality of life for individualpatients but also indicate that important andsubstantial economic savings may arise from using thistechnology.
As yet no definitive published data are available on the effects of biventricular pacing on mortality, but sev-eral studies with end points of cardiac and all cause Fig 3 Fluoroscopy showing final lead positions of an
atrio-biventricular implantable cardiac defibrillator in an
mortality remain in progress.17 18 The cardiac resyn- antero-posterior projection (RA=right atrial lead; RV ICD=right chronisation in heart failure (CARE-HF) study has ventricular implantable defibrillator lead; LV=left ventricular coronary recently completed recruitment of patients, whereas sinus lead). Used with permission from the authors (AWCC) the preliminary findings of the comparison of medicaltreatment, pacing, and defibrillation in chronic heart ejection fraction and cardiac output while working less failure (COMPANION) study, which randomised over and consuming less oxygen.14 In addition, reintroduc- 1600 patients to medical treatment alone, to biven- ing left ventricular synchrony can increase left tricular pacing, and to biventricular implantable ventricular filling times, decrease pressure on the cardiac defibrillators have been announced. This study pulmonary capillary wedge, and reduce mitral regurgi- was halted prematurely because of a 20% reduction in tation (box 1). More advanced devices now enable all cause mortality and all cause admissions to hospital manipulation of both atrioventricular and interven- in the groups receiving biventricular pacing. The most tricular pacing intervals and the potential to further notable benefits were seen in the arm of the study in optimise individual haemodynamic and functional which patients received biventricular implantable cardiac defibrillators, where a 40% reduction of allcause mortality was achieved. Publication of the full Clinical trials of biventricular pacing
report is eagerly awaited, but these preliminary data Clinical trials have shown that biventricular pacing is indicate that biventricular pacing may confer impor- effective in the treatment of heart failure patients with left bundle branch block (table). Several randomisedcontrolled clinical trials have compared biventricularpacing with medical treatment on its own. Both themultisite stimulation in cardiomyopathies (MUSTIC) Box 2: Who should be considered for
and the multicentre insync randomised clinical evalua- biventricular pacing
tion (MIRACLE) studies, which enrolled 68 and 524 heart failure patients, respectively, in a randomised crossover trial of biventricular pacing showed signifi- • Highly symptomatic (New York Heart Association cant improvements in quality of life scores, exercise tolerance, New York Heart Association functional class, peak oxygen uptake, and cardiac ejection fraction during biventricular pacing.15 16 What was particularly Left bundle branch block wide QRS >130 ms/echo assessment impressive was the reduction in admissions to hospital Induced by right ventricular apical pacing for worsening heart failure seen in the MIRACLE study. At six months the relative risk of decompensated heart failure requiring admission to hospital was Limitations and complications of biventricular
Box 1: Haemodynamic effects of biventricular
The electrocardiogram is used as the screening tool for • Increased left ventricular ejection fraction and predicting ventricular dyssynchrony and hence suit- ability for biventricular pacing. Up to 20% of patients fulfil the criteria for biventricular pacing (box 2), yet • Prolonged diastole and left ventricular filling time derive little or no clinical benefit from resynchronisa- • Reduced left ventricular end diastolic and end tion.19 In the future, more sensitive and specific non-invasive screening tests will be required to • Increased left ventricular synchrony and pulse improve the selection of patients. This will probably be in the form of echocardiography guided techniques such as tissue Doppler echocardiography, which facili- • Decreased pulmonary capillary wedge pressure tates the quantification of dyssynchrony20 and thus may provide more accurate prediction of a favourableclinical response with biventricular pacing.
BMJ VOLUME 326 17 MAY 2003
Clinical trials of atrio-biventricular pacing No of patients
Inclusion criteria
End points
Increased*(Similar benefits seen withCRT and univentricular (LV)stimulation) Left ventricular ejection fraction <35% owing to survival benefits withcardiac resynchronisation andICD arms.
Full results expected 2003 New York Heart Association scoreQuality of life scoreNeurohormonal In all trials, patients were having optimal medical treatment; outcomes were compared with baseline.
Even with improvements in delivery systems and Implantable cardioverter defibrillators
pacing lead technology the site of left ventricular Severe left ventricular dysfunction is now known to be pacing is often limited by the individual’s coronary an independent predictor of cardiac mortality. Death is venous anatomy. Implantation of ventricular pace- usually attributable to progressive heart failure or the makers can be technically challenging and is associated development of malignant ventricular arrhythmias.
with small risks. Inability to deploy the left ventricular Several large randomised controlled trials have found lead accounts for most of the 8% reported implant fail- a sizeable reduction in mortality among patients with ures.16 Commonly encountered complications over ischaemic heart disease, impaired left ventricular func- and above those associated with any permanent pace- tion, and failed sudden death or evidence of ventricular maker insertion are usually related to the insertion of arrhythmias who had an implantable cardiac defibrilla- the left ventricular lead. These include inability to tor compared with patients treated with antiarrhythmic intubate the coronary sinus or a venous tributary, drugs.21 22 This compelling evidence has formed the dissection of the coronary sinus, displacement of the basis for guidance from the National Institute for left ventricular lead, and diaphragmatic stimulation Clinical Evidence (NICE) on widespread use of these (box 3). Complications are largely minimised by the devices in individuals at high risk.23 The role of operator’s experience, meticulous technique, stringent implantable cardiac defibrillators in patients with non- testing at implantation, and careful programming of ischaemic cardiomyopathy is less certain but should be addressed by the ongoing sudden cardiac death inheart failure trial, which includes patients with bothischaemic and non-ischaemic cardiomyopathy. In the Box 3: Limitations of the technique
most recently published multicentre automatic defi- • Selection of patients and prediction of patients’ brillator implantation II (MADIT II) trial,24 no formal assessment of arrhythmic risk was required; the inclusion criteria were based on the presence of ischaemic heart disease and poor left ventricular function alone. The trial was stopped early because of a relative risk reduction of 31% in all cause mortality seen in the group treated with implantable cardiac defibrillators compared with controls over a 20 month follow up period. The implications of this trial alone may expand the recommended indications forimplantation of these devices in the future.
BMJ VOLUME 326 17 MAY 2003
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. Theeffect of spironolactone on morbidity and mortality in patients with Additional educational resources
severe heart failure. Randomized Aldactone Evaluation Study Investiga-tors. N Engl J Med 1999;341:709-17.
• The website of the North American Society of Cowie MR, Fox KF, Wood DA, Metcalfe C, Thompson SG, Coats AJ, et al.
Pacing and Electrophysiology (www.naspe.org) gives Hospitalization of patients with heart failure: a population-based study.
Eur Heart J 2002;23:877-85.
useful general information on recent developments Cowie MR, Wood DA, Coats AJ, Thompson SG, Suresh V, Poole-Wilson and current guidelines for heart failure devices PA, et al. Survival of patients with a new diagnosis of heart failure: a • www.docguide.com is a general website citing recent population based study. Heart 2000;83:505-10.
Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, et al.
literature, which has several links for cardiac Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determi- • The official website of the National Institute for nants of prognosis in heart failure. The V-HeFT VA Cooperative StudiesGroup. Circulation 1993;87:VI5-16.
Clinical Excellence (www.nice.org) provides full and Hochleitner M, Hortnagl H, Ng CK, Hortnagl H, Gschnitzer F, Zechmann abbreviated guidelines for the use of implantable W. Usefulness of physiologic dual-chamber pacing in drug-resistant idio- pathic dilated cardiomyopathy. Am J Cardiol 1990;66:198-202.
10 Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L.
• www.medtronic.com/physician/cardiology.html is an Results of atrioventricular synchronous pacing with optimized delay in extensive website of a major device company, with patients with severe congestive heart failure. Am J Cardiol 1995;75:919- sections for doctors and patients, and covers all aspects 11 Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, et al.
of current pacing technologies used for heart failure Multisite pacing for end-stage heart failure: early experience. Pacing ClinElectrophysiol 1996;19:1748-57.
12 Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function ofpaced patients with congestive heart failure. The Pacing Therapies for In the light of trials showing a reduction in Congestive Heart Failure Study Group. The Guidant Congestive Heart mortality with implantable cardiac defibrillators and Failure Research Group. Circulation 1999;99:2993-3001.
13 Daubert JC, Ritter P, Le Breton H, Gras D, Leclercq C, Lazarus A, et al.
improvement in left ventricular function with biven- Permanent left ventricular pacing with transvenous leads inserted into tricular pacing in patients with heart failure it seems the coronary veins. Pacing Clin Electrophysiol 1998;21:239-45.
14 Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, et al. Left logical that combined biventricular pacing and ventricular or biventricular pacing improves cardiac function at implantable cardiac defibrillators devices may be com- diminished energy cost in patients with dilated cardiomyopathy and leftbundle-branch block. Circulation 2000;102:3053-9.
plementary in selected patients. The early indications 15 Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al.
from the COMPANION trial support this theory, with Effects of multisite biventricular pacing in patients with heart failure andintraventricular conduction delay. N Engl J Med 2001;344:873-80.
the greatest reduction in mortality observed with com- 16 Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al.
bined devices. Although final reports are yet to be pub- Cardiac resynchronization in chronic heart failure. N Engl J Med2002;346:1845-53.
lished on prospective trials incorporating combined 17 Bristow MR, Feldman AM, Saxon LA. Heart failure management using biventricular pacing and implantable cardiac defibrilla- implantable devices for ventricular resynchronization: comparison of tors devices, the use of combined devices to provide medical therapy, pacing, and defibrillation in chronic heart failure(COMPANION) trial. COMPANION Steering Committee and COM- both cardiac resynchronisation with defibrillation are PANION Clinical Investigators. J Card Fail 2000;6:276-85.
18 Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The CARE-HF study (CArdiac REsynchronisationin Heart Failure study): rationale, design and end-points. Eur J Heart Fail2001;3:481-9.
19 Reuter S, Garrigue S, Barold SS, Jais P, Hocini M, Haissaguerre M, et al.
Comparison of characteristics in responders versus nonresponders withbiventricular pacing for drug-resistant congestive heart failure. Am J Car- Evidence is now compelling that pacing technologies 20 Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricu- can improve morbidity and mortality in patients with lar systolic and diastolic asynchrony in patients with congestive heart fail- heart failure. The indication for using these devices is ure and normal QRS duration. Heart 2003;89:54-60.
21 The AVID Investigators. A comparison of antiarrhythmic drug therapy likely to expand in the future. Clinicians at all levels with implantable defibrillators in patients resuscitated from near fatal should have a fundamental knowledge of the ventricular arrhythmias. N Engl J Med 1997;337:1576-83.
indications and function of these devices. The growth 22 Moss AJ, Jackson-Hall W, Cannom DS, Daubert JP, Higgins SL, Klein H, et al. Improved survival with an implanted defibrillator in patients with in these technologies will also have serious economic coronary disease at high risk for ventricular arrhythmia. N Engl J Med implications for those planning and delivering health 23 National Institute for Clinical Excellence. Guidance on the use of implantable cardioverter defibrillators for arrhythmias. Technology appraisal guidance 11.
London: NICE, 2000.
24 Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Pro- Competing interests: AWCC has received reimbursement from phylactic implantation of a defibrillator in patients with myocardial many companies for attending conferences. REL receives a infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83.
research fellowship from Medtronic Inc and has received reim- bursement from many companies for attenting conferences.
MRC is the clinical adviser for the national clinical guidelines onthe management of heart failure, commissioned by the National Institute for Clinical Excellence, but the opinions in this revieware his own and will not necessarily reflect those in theforthcoming guideline. MRC has received honorariums for Human dignity
advisory boards and lectures related to treatments mentioned in Among other living things, it is man’s dignity to value certain ideals above comfort, and even abovelife. This human trait makes of medicine aphilosophy that goes beyond exact medical Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-Wilson PA, SuttonGC, et al. The epidemiology of heart failure. Eur Heart J 1997;18:208-25.
sciences, because it must encompass not only man Berry C, Murdoch DR, McMurray JJ. Economics of chronic heart failure.
as a living machine but also the collective Eur J Heart Fail 2001;3:283-91.
Kjekshus J, Swedberg K, Snapinn S. Effects of enalapril on long-termmortality in severe congestive heart failure. CONSENSUS Trial Group.
René Jules Dubos (1901-81), French/American microbiologist, in Mirage of Health Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al.
Effect of carvedilol on the morbidity of patients with severe chronic heart Robert Richardson, medical historian, Chichester failure: results of the carvedilol prospective randomized cumulativesurvival (COPERNICUS) study. Circulation 2002;106:2194-9.
BMJ VOLUME 326 17 MAY 2003

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Diário da República, 2.ª série — N.º 114 — 15 de Junho de 2007do disposto no artigo 241.º da Constituição da República Portuguesa,do artigo 64.º, n.º 7, alínea a) da Lei n.º 169/99, de 18 de Setembroe do artigo 55.º da Lei n.º 2/2007, de 15 de Janeiro. O RTEDUL tem por objectivo o ordenamento da utilização da viapública, quer na circulação, quer no parqueamento de veíc


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