Heart Failure · a major pathophysiological role in heart failure. Alhough these systems provide...

205

Dialogues in Cardiovascular Medicine - Vol 9 . No. 4 . 2004

Lead Article The evolving rationale of heart failure therapy - L. Tavazzi, E. Arbustini 207

Expert Answers to Three Key Questions Cardiac resynchronization therapy in heart failure: which type and for whom?A. Auricchio, C. Fantoni 225

Multiple neurohormonal modulation: what are the most effective combinations? - M. Komajda 232

Why are we unable to completely control the activation of neurohormonal systems in chronic heart failure—and should we? - H. Drexler, K. C. Wollert 238

Fascinoma Cardiologica Trails of Discovery: Class III antiarrhythmic agents: serendipity or drug design?J. D. Fitzgerald 243

Summaries of Ten Seminal Papers - M. Faircloth, J. Clark, M. Marber 253

Heart Failure

Familial dilated cardiomyopathy: from clinical presentation tomolecular genetics – A. Arbustini and others

Randomized trial of an education and support intervention to prevent readmission of patients with heart failureH. M. Krumholz and others

Long-term trends in the incidence of and survival with heartfailure – D. Levy and others

Differential gene expression and genomic patient stratificationfollowing left ventricular assist device support – B. C. Blaxall

and others

Clinical assessment identifies hemodynamic profiles that predictoutcomes in patients admitted with heart failure – A. Nohria

and others

Effect of enalapril on 12-year survival and life expectancy inpatients with left ventricular systolic dysfunction: a follow-upstudy – P. Jong and others

Targeted anticytokine therapy in patients with chronic heartfailure: results of the Randomized Etanercept WorldwideEvaluation (RENEWAL) – D. L. Mann and others

Regenerative capacity of the myocardium: implications fortreatment of heart failure – R. von Harsdorf and others

Do we understand who benefits from resynchronisation therapy? – O. A. Breithardt and others

Hypertrophic cardiomyopathy – P. Elliott and W. J. McKenna

Bibliography of One Hundred Key Papers 265

Schematically, over the last 30 years, there havebeen at least three different models for inter-preting heart failure, which have led to differentapproaches to the treatment of this syndrome.1

In the 1970s, heart failure was seen as the clinical man-ifestation of heart pump failure causing a drop in renalblood flow, thus resulting in water retention. Therapywas based on drugs that could potentiate myocardialcontractility (digitalis) and limit fluid retention (diuret-ics). In the 1980s, the prevailing interpretation wasthat heart pump failure caused diffuse vasoconstriction.The resulting blood flow limitation increased the workof the heart and compromised the function of organsand peripheral districts. Treatment, therefore, placedthe emphasis on vasodilators, in addition to diureticsand digitalis. New classes of drugs emerged, amongwhich the phosphodiesterase inhibitors (amrinone,milrinone, etc). These drugs were capable of both stim-ulating myocardial contractility and dilating the ves-sels. However, they appeared to be more harmful thatbeneficial in long-term treatment. In the 1990s, atten-tion focused on the hyperactivity of regulatory systems,such as the renin-angiotensin-aldosterone system(RAAS) and the adrenergic system, which were ascribeda major pathophysiological role in heart failure.

Alhough these systems provide effective short-termprotection of cardiocirculatory function in the presenceof dehydration or hemorrhage, they were shown to bedeleterious in the long term. The 1990s also saw thebeginning of systematic evaluation of drug efficacyand safety in clinical trials conducted on large popula-tions, which confirmed without the slightest doubtthe clinical efficacy of RAAS and adrenergic systemmodulation. Thus, heart failure today is understood asthe ultimate common outcome of many forms of heartdisease at the advanced stage. This implies a greatcomplexity in the pathogenesis and evolution of theheart failure process, in which two main features playan essential role: (i) ventricular remodeling, whichcauses progressively worsening systolic and diastolicventricular dysfunction; and (ii) activation of a series ofbiological responses to ventricular dysfunction, whichcontribute to determining the clinical expression and


207

The evolving rationale of heart failure therapyLuigi Tavazzi, MD, FESC, FACC; Eloisa Arbustini, MD, FESC

Department of Cardiology - Policlinico S. Matteo - Institute of Care and Research (IRCCS) - Pavia - ITALY

Current heart failure rationales bear little resemblanceto the pump failure model that prevailed in the 1970s,prompting prescriptions of digitalis to potentiate my-ocardial contractility and diuretics to decrease fluidretention. First, the 1980s focused on the feature ofdiffuse vasoconstriction and added vasodilators to thetherapeutic regimen. Then a conceptual leap in the1990s revealed the role of regulatory system hyperac-tivity, inspiring a range of renin-angiotensin-aldo-sterone and adrenergic system modulators with multi-faceted and still unexhausted pharmacodynamicpotential. Models, medicines, and an increasing wealthof devices have since driven each other forward to cre-ate the current plethora of complementary rationales.The macroscopic ventricular remodeling responsiblefor deteriorating ventricular dysfunction is related tomicroscopic disruption of the connective tissue matrix,since both features respond to angiotensin-convertingenzyme therapy. Other models, each with an actualor, more often, potential therapeutic correlate, includethe early role of diastolic dysfunction, ventricular de-synchronization, the contribution of myocardial smallvessel and endothelial disease revealed in hypertensiveand diabetic heart failure, and the critical impact ofcardiomyopathy genes and their differential expressiondepending on clinical circumstance. Unfortunately,these interdigitating narratives have yet to be gener-ally mirrored in a seamless system of efficient heartfailure care.

Keywords: heart failureAddress for correspondence: Prof Luigi Tavazzi, Primario Divisione di Cardiologia, Policlinico S. Matteo, Piazzale Golgi 2, 27100 Pavia, Italy(e-mail: [email protected])

Dialogues Cardiovasc Med. 2004;9:207-222

evolution of heart failure. The current treatment ofheart failure, laid down in the guidelines of the majorinternational Cardiology Societies, addresses the lat-est pathophysiological concepts. Nevertheless, clini-

cal and scientific experience over the past several yearshas highlighted the limitations as well as the benefitsof the current therapeutic approach and of the concep-tual model on which it is based.

HOW EFFECTIVE IS THERAPY?

The most common way of reporting the benefit oftreatment in mortality trials is the reduction in deathsoccurring during the observation period, either in ab-solute terms (number of deaths less for every 100 sub-jects in 1 year and/or during the observation period)or in relative terms (percentage of deaths less in thetreated population in relation to control subjects).There is much talk of lives saved and of the numberof subjects needed to treat to prevent 1 death (NNT).It would sometimes appear as though this life weresaved “for ever!” Obviously, this is not the case. Heartfailure usually persists and life has only been prolonged.By how much? This is the real question to ask. To an-swer this, we need to know how long all the patients,both treated and untreated, live. Furthermore, sincecontrol patients will also be treated, at the end of thestudy, if the treatment is shown to be effective, themean difference in survival of the two groups reflectsthe efficacy of the treatment during the period of thestudy, when the treatment was randomized. In thiscontext, the First COoperative North ScandinavianENalapril SUrvival Study (CONSENSUS I) reported anaverage of 9 months additional life over a mean periodof treatment with captopril of less than 1 year.2 Thiswas a dramatic finding in view of the severity of heartfailure in the patients enrolled in CONSENSUS, inwhom the annual mortality rate was about 50%. Curi-ously, similar results were found when estimating theincrease in survival of patients enrolled in the treat-ment arm of the Studies Of Left Ventricular Dysfunction(SOLVD-treatment), with an ejection fraction (EF) <35%and symptoms of heart failure, and in the preventionarm (SOLVD-prevention) (with EF <35% without symp-toms of heart failure) trials.3 This was only an estimate,with wide confidence limits, and not a measurement,since when the calculation was carried out, 12 yearsafter the start of the study, not all the patients haddied. The estimate showed that SOLVD conferred anaverage of about 9 additional months of life on patientstreated with enalapril for a mean period of randomizedtreatment of 3 years. Taking into account the fact thatafter the first months2 or the first year3 of randomizedtreatment the survival curves of patients treated withACE inhibitors and of the controls tended to becomeparallel, what we can reasonably expect from angio-tensin-converting enzyme (ACE) inhibitor treatment


The evolving rationale of heart failure therapy - Tavazzi and Arbustini

208

SELECTED ABBREVIATIONS AND ACRONYMS

ARB angiotensin-receptor blocker

CHARM Candesartan in Heart failure Assess-ment in Reduction of Mortality

CONSENSUS I First COoperative North Scandina-vian ENalapril SUrvival Study

CRP C-reactive protein

DCM dilated cardiomyopathy

DEFINITE DEFibrillators In Non-Ischemic cardiomyopathy Treatment Evaluation

EF ejection fraction

EUROPA EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

HCM hypertrophic cardiomyopathy

HOPE Heart Outcomes Prevention Evaluation

ICD implantable cardioverter defibrillator

LVEF left ventricular ejection fraction

MI myocardial infarction

PUFA polyunsaturated fatty acid

QUASAR QUinapril Anti-ischemia and Symp- toms of Angina Reduction

QUO VADIS Effect of QUinapril On Vascular ACE and Determinants of ISchemia

RAAS renin-angiotensin-aldosterone system

RCM restrictive cardiomyopathy

REVIVE Randomized, multicenter, EValuation of Intravenous leVosimendan Effica-cy vs placebo in the short-term treat-ment of decompensated chronic heart failure

SCD-HeFT Sudden Cardiac Death in Heart FailureTrial

SOLVD Studies Of Left Ventricular Dysfunction

SURVIVE Multicenter, parallel-group randomized,double-blind, double-dummy studyin patients with acutely decompen-sated heart failure comparing the efficacy of levosimendan with that of dobutamine

TNF-α tumor necrosis factor–α

in heart failure from these two trials is under 1 extrayear of life. It should be noted that these patients werenot treated with β-blockers.

Similar considerations also apply to device-basedtreatment, particularly in the case of implantable de-fibrillators, whose only function is, precisely, the pre-vention of sudden arrhythmic death. The only studycarried out to date in patients with heart failure is thestill unpublished Sudden Cardiac Death in Heart Fail-ure Trial (SCD-HeFT). In this study, the reduction ofmortality was about 1.7%/year in absolute values for atotal of about 8 deaths less over an observation periodof approximately 5 years. How much longer these pa-tients lived (in relation to their natural destiny) is un-known. We do, however, know that, over 5 years, 92 pa-tients out of 100 derived no benefit from the treatmentdespite being exposed to the risk of possible complica-tions or inappropriate shocks delivered by the device.Thus, for example, the recently published DEFibrillatorsIn Non-Ischemic cardiomyopathy Treatment Evalua-tion (DEFINITE) study recorded inappropriate shocksin 46 patients and appropriate shocks in 41 patients4).We mention SCD-HeFT not because it is the only trialof its kind in heart failure patients, but also becauseof its relatively long observation period. As Salucke etal recently pointed out, studies with relatively shortobservation periods can lead to underestimation of thereal benefit of defibrillators.5 Identification of patientsat genuine high risk is clearly critical for an appropriateindication for defibrillator use. In other words, prog-nostic stratification needs to be improved.

PROGNOSTIC STRATIFICATION

The fact that heart failure guidelines contain only afew inconclusive lines on prognostic stratification is nomere oversight. European guidelines list a series ofsupposedly independent prognostic predictors.6 How-ever, despite the many prognostic indicators and algo-rithms that have been proposed,7 our ability to providesatisfactory prognostic evaluation remains extremelylimited. A number of explanations for our impotencehave been put forward.6 I will briefly discuss severalof these.

• The numerous pathologies that lead to heart failureevolve in their own specific way. This fact, which neces-sarily affects the progression of the cardiac syndrome,is not taken into account by the indicators usually usedin the prognostic stratification of heart failure.• Associated comorbid conditions, in particular in theelderly, can produce clinical profiles and disease evo-

lutions that are not consistent with the algorithmsbased on trial data, inasmuch as patients with comor-bid diseases are usually excluded from trials. • Investigation of the biological systems involved in theprogression of heart failure is limited by our ability tomeasure the key variables of these very systems. Atmost, we measure the blood concentrations of the me-diators, but many of them have paracrine functions andvery short lives. As only a small fraction of these me-diators enters the circulation, blood concentrationsdo not reflect levels of activity in the tissues.• The activation of many biological systems and theirimpact on organs and tissues in heart failure is notgradual and constant over time. Furthermore, the prog-nostic power of indicators can differ in relation to thestage of evolution of the syndrome. Powerful indicatorsat earlier stages of the syndrome (eg, left ventricularejection fraction [LVEF]), lose some of their predictivestrength at more advanced stages, while others assumegreater importance (eg, organ damage indicators orright ventricular dysfunction). Clinical destabilizationmay occur abruptly and regress rapidly. Prognostic strat-ification yields very different results depending onwhether the patient is in a stable or unstable phase.Therefore, one set of predictive algorithms should beused for making immediate decisions during acutephases and different one for defining long-term strate-gies during stable periods.• About half of the deaths in patients with heart fail-ure are sudden and can occur at any stage of the syn-drome’s evolution, a fact that traditional algorithmsfail to address. In other words, we lack strong indicatorsfor sudden death. • The introduction of new treatments into clinical prac-tice can have a marked effect of both outcome andsymptoms, but not necessarily simultaneously. For thisreason, algorithms for prognostic stratification shouldbe updated in relation to the treatments used and theindividual application of algorithms should take intoaccount the therapy used in the individual patient.

Alongside these general methodological considera-tions, others concern individual aspects of prognosticstudies reported in the literature, including more orless restrictive inclusion criteria, numerically inade-quate series, and the restriction of parameters includedin multivariate analyses, such that the independentvalue of the prognostic indicators selected is oftenquestionable.

Obviously, prognostic limitations in turn impose a sub-stantial limitation on the successful identification ofthe potential responders to available treatments. It will



209

not have escaped attentive clinicians that althoughguidelines were issued recommending the prescriptionof ACE inhibitors and β-blockers to all patients, no for-mal recommendations could be given regarding neu-rohormonal prognostic predictors usable in clinicalpractice. Brain natriuretic peptide (BNP) is a cardiachormone that is only indirectly involved in modulatingthe major systemic regulatory systems. This may notbe very relevant for some treatments targeted at thefundamental pathophysiological mechanisms of heartfailure, in particular those shown to be effective in boththe prevention and treatment of heart failure whateverthe severity, but it certainly is relevant for those treat-ments reserved to patients with specific risk factors,typically of sudden death. Since it is generally thoughtthat the risk of sudden arrhythmic death is relativelyhigher in the numerous patients with heart failure inthe less advanced New York Heart Associated (NYHA)classes, although recent data contradict this assump-tion,8 a reliable definition of the risk of sudden deathis essential. Thus, prognostic stratification, based ondatabases of randomized trials, and particularly, ofregistries and observational studies, must be consid-ered a primary aim.

TREATMENT PRIORITIES: THE HEART, THE REGULATORY

SYSTEMS, OTHER ORGANS, OR COMPROMISED TISSUES?

The obvious answer, “all,” is not the correct one. Prior-ities should be strictly based on benefits versus risks,new drugs should developed with compliance as amajor goal, and therapeutic research should focus at-tention and resources on clearly defined objectives.

The heart

As far as the heart is concerned, Table I lists what I be-lieve are the fundamental mechanisms of pump failure,together with their respective therapeutic implications.The most obvious pathophysiological aspect is pumpfailure associated with the inability of myocytes to gener-ate a force sufficient to ensure efficient and appropri-ate circulation of the blood to meet the needs of thebody. Treatment should increase the contractile forceof myocytes without causing notable side effects. Sofar, however, all tested long-term oral inotropic drugshave invariably increased mortality. As for intravenousinotropic drugs (whether β-receptor stimulators suchas dobutamine or phosphodiesterase III inhibitors suchas milrinone and amiodarone), their most significantlimitation is due to the fact that their inotropic action

is expressed through increased availability of intracel-lular calcium. Since calcium also has important elec-trophysiological actions, any increase in the concentra-tion of calcium causes changes in ion flows, facilitatingthe onset of potentially fatal arrhythmias. A new classof drugs, the calcium sensitizers—prototype: levosi-mendan—claims to increase myocardial inotropismwithout inducing dangerous ionic imbalances. Initialclinical trial data appear to support this hope.9,10

Two large prospective mortality-morbidity trials withlevosimendan, the first versus placebo (REVIVE [Ran-domized, multicenter, EValuation of Intravenous leVosimendan Efficacy vs placebo in the short-termtreatment of decompensated chronic heart failure]),the second versus dobutamine (SURVIVE), are current-ly under way and should provide a definitive answer.

The aspect that I believe has been less clearly appre-ciated so far is disruption of the connective tissue matrix.This is a fundamental mechanism of heart failure inmost cases of hereditary dilated cardiomyopathies(DCMs), which definitely also plays an important rolein ischemic cardiomyopathy. It leads to an increase(not a decrease) in ventricular compliance, shifting theentire ventricular pressure-volume curve to the right,resulting in greater dilatation of the chamber for small-er pressure loads. Although Starling’s law should fullyapply in this case, the problem is that part of the forcegenerated by the myocytes is not transmitted becauseof changes in intercellular connective tissue bridges,and is therefore lost because it does not contribute toproducing the overall mechanical energy expressedby the ventricles. We do not have drugs “designed” tocounteract disruption of the connective tissue matrix,but it is likely that some of the benefit of drugs modi-fying the renin-angiotensin system and of antialdo-sterone drugs is linked to this mechanism.

The third mechanism of heart failure is ventricular dys-synchrony. The severely compromised ventricular me-chanics leading to heart failure can be characterized byfunctional desynchronization of the two ventricles dueto a disorder of intraventricular conduction (usually leftbundle branch block) or to changes in the mechanicalcoordination of the left ventricle. Under these condi-tions, myocardial regions contracting against each otherearly waste energy in inefficient movements, and re-gions that do so late waste it in overcoming the undulyhigh resistances. The therapeutic approach is ventricu-lar resynchronization by elective multisite stimulation.

The fourth form of heart deficit is ventricular diastolicdysfunction. It has now become essential to differenti-



210

ate heart failure into forms with depressed left ven-tricular systolic function and those with preserved leftventricular function, that is, with an EF less than orgreater than ≈45%, respectively. Whether therapy shouldbe radically different in relation to ventricular systolicfunction, in practice in relation to left ventricular ejec-tion fraction, is not yet clear. Apart from the results ofthe Candesartan in Heart failure Assessment in Reduc-tion of Mortality (CHARM)-preserved study (which didnot show any added value of the angiotensin receptorblockers [ARBs]),11 data from the various ongoing trialstesting different classes of drugs in heart failure withpreserved systolic function are not yet available. Theclinical profile of these patients seems to be relativelyspecific: higher prevalence among the elderly, women,hypertensive, diabetics with a relatively good function-al class in stable conditions, but with a tendency toabrupt destabilizations during which left ventricular EFtends to remain almost normal; these patients maybe relieved relatively easily with the administration ofdiuretics and vasodilators. The prognostic data areconsistent with this profile: less mortality than amongpatients with a low EF, but a similar incidence of hos-pital admissions. It is probable that ongoing studieswill show that pharmacological control of the regulato-ry systems needs not be very different from that in pa-tients with a reduced EF, but that direct interventionsto the heart should differ. Drugs that prevent progres-sive fibrosis of the heart (the antialdosterones?) couldalso, or above all, be particularly effective in theseforms. Furthermore, it seems essential to prevent desta-bilizations, prevalently caused by pulmonary conges-tion, which does, in fact, dominate this clinical picture.Since the left ventricle is less elastic (in the first phaseof diastole) and less compliant (in the late phase ofdiastole) than normal, it adapts poorly to volume loads.A modest increase in volume load is not accepted bythe rigid left ventricle, causing a considerable increase

in pulmonary pressure, which can trigger acute pul-monary edema. Relieving the congestion with a moder-ate dose of intravenous diuretics can rapidly resolvethe destabilization, which in turn can reduce the riskassociated with these episodes and contribute to aless severe prognosis.

Why should the diastolic properties of the heart beprevalently altered in some diseases? Do alterationsin small vessel function play an important role? Hyper-tension is a disease of the arteries that secondarilyaffects the heart. When and why, as well as in whom,hypertension becomes a cardiac disease is still far fromclear. The scope for prevention might be enormous ifresearch would focus on the heart and small myocar-dial vessels as well as on the arteries. New perspectivesshould include existing drugs and new molecular play-ers in hypertrophy and remodeling, such as melusin,a protein whose absence in the hypertrophic heartseems to condition dilation and heart failure.12 The mi-crocirculation also represents a major research fieldand substrate of treatment in diabetic patients. Dia-betes-related heart disease is currently considered asthe result of coronary artery disease (CAD) electivelycomplicating the natural history of diabetes. Further-more, although more than twenty genetically differenttypes of diabetes are known, our current approach onlygroups patients into those affected by insulin-depend-ent or non–insulin-dependent diabetes, mostly becausetreatments are exclusively based on either insulin ororal hypoglycemic drugs.

Small-vessel disease and endothelial dysfunction aremajor contributors to myocardial damage in both hy-pertension and diabetes. The increasing use of positronemission tomography (PET) scan could increase ourknowledge of small-vessel disease and open up newareas of research for protecting the myocardium. Small-



211

Effect

• Loss of contractile function

• “Too” compliant ventricles Inadequate/erratic transmissionof the force generated by the myocytes

• Atrioventricular inter/intraventric-ular incoordination

• Poorly relaxing, stiff ventricles, limited ventricular filling

Table I. Mechanisms, effects, and treatment of major cardiac function alterations in chronic heart failure.

Mechanism

• Bioenergetic decline of myocytes

• Disruption of the collagen matrix

• Cardiac dyssynchrony

• Alterations of relaxation and elastic properties

Treatment

• Inotropic drugs

• No specific treatment, neurohor-monal agents?

• Multisite pacing

• Unloading, atrial contribution, andadequate diastolic interval

vessel disease may either contribute to left ventricularhypertrophy via an imbalance between myocyte hyper-trophy, hyperplasia, and apoptosis or impaired my-ocardial perfusion. Prevention of heart failure shouldtherefore be based on the preservation of structuraland functional integrity of the myocardial tissue. Sys-tolic dysfunction comes later and its improvement isa late strategy. Elucidation of the role of small-vesseldisease in myocyte apoptosis and collagen productionand turnover may initiate a translational paradigm shiftin clinical practice.

The regulatory systems

As already mentioned, among the various regulatorysystems, we are able to therapeutically manipulate theRAAS and the adrenergic system. One of the ways ofdoing this is to modulate some of the many functionsof the endothelium. Analysis of the clinical effects pro-duced by ACE inhibitors in ischemic heart disease, themost common cause of heart failure, gives a clear in-dication of the extent to which the counterregulatoryactions of drugs can be selective.

The pharmacological treatment of stable angina hastwo major purposes. The first is to prevent myocardialinfarction (MI) and death and thereby increase thequantity (duration) of life. The second is to reduce thesymptoms of angina and the occurrence of ischemia,which should improve the quality of life. Accordingly,there are two categories of treatment: those prescribedto prevent death and MI and those with antianginal andanti-ischemic effects aimed at alleviating symptomsand reducing ischemia.13 Obviously the two categoriespartially overlap. The first group of drugs includes an-tiplatelet agents, antithrombotic therapy, antihyperten-sive agents, lipid-lowering agents, and ACE inhibitors;the second group includes β-blockers, calcium antag-onists, and nitrates.

After having been tested with success in heart failure,systemic hypertension, and acute and subacute MI,the ACE inhibitors were tried in patients considered tobe at risk for cardiovascular events in both the HeartOutcomes Prevention Evaluation (HOPE)14 and EU-ropean trial on Reduction Of cardiac events with Perin-dopril in stable coronary Artery disease (EUROPA)15

trials. The effectiveness and safety of ramipril and perin-dopril, respectively, were clearly demonstrated, even inpatients who were not hypertensive. The EUROPA trialis particularly relevant in this context because it specif-ically enrolled patients with chronic ischemic heartdisease, since the criterion for inclusion in the study

was confirmed presence of CAD associated with anylevel of risk. Given that some ACE inhibitors (ramipriland perindopril) have been shown to effectively preventthe clinical progression of coronary atherosclerosis,one may wonder whether these drugs are also effectivein reducing the ischemic burden of patients with CADand inducible myocardial ischemia. About twenty smallpublished studies suggest that these drugs are indeedeffective in this context. However, two recent random-ized studies demonstrated the opposite. The QUinaprilAnti-ischemia and Symptoms of Angina Reduction(QUASAR) trial16 sought to determine whether an ACEinhibitor prevents transient ischemia (exertional andspontaneous) in patients with CAD and stable angina.Three hundred and thirty-six patients without hyper-tension, left ventricular dysfunction, or previous MIwere randomly assigned to quinapril or placebo groups.After 8 weeks, the groups did not differ at all in termsof indices assessing myocardial ischemia, such as is-chemic threshold during exercise, ischemic burdenfrom ambulatory recordings, and scores on the SeattleAngina Questionnaire. These findings match those fromanother trial, the Effect of QUinapril On Vascular ACEand Determinants of ISchemia (QUO VADIS) study,17

carried out in 149 patients with ischemic heart diseaserandomized to quinapril or placebo 4 weeks beforeelective bypass surgery and then followed for 1 year.Again, no differences in ischemic measures were ob-served between the two groups. Although clinical eventswere obviously not end points in this small trial, it isinteresting to note that fewer adverse cardiovascularevents were recorded in the quinapril group than inthe placebo group (4% vs 15%, P=0.02). Though theabsence of any effect of quinapril on ischemic param-eters may be related to the dose of the drug, or to different effects (or lack of effects) of different ACE in-hibitors, the complex scenario of the action of ACEinhibitors in ischemic heart disease suggests that thereis a clear distinction between antianginal and anti-atherosclerotic-antithrombotic drugs, the former beingeffective in reducing the ischemic burden, but havinglittle or no effect on progression of the coronary arterydisease, the latter having little or no effect on the is-chemic burden, but significantly modulating the pro-gression of the coronary artery disease.

The other major system activated in heart failure, theimmune-inflammatory system, is not currently control-lable. This system is partly also responsible for theprogression of ischemic heart disease, and thus relevantin heart failure secondary to ischemic heart disease.Vasan et al recently explored the predictive value of in-terleukin 6 (IL-6), tumor necrosis factor–α (TNF-α), and

212



C-reactive protein (CRP) on the onset of congestiveheart failure in older subjects without previous MI.18

They showed a strong predictive value for all the mark-ers, particularly for IL-6. Similar findings were reportedby Koukkunen et al19 and Cesari et al20 exploring theprognostic value of these three inflammatory markersin older patients with CHD, perhaps, because of theirwide range of actions including effects on platelets, en-dothelium, and factors of metabolism and coagulation.TNF-α and IL-6 levels are associated with the severityof left ventricular dysfunction and with the degree ofactivation of the sympathetic and renin-angiotensinsystems. It has also been reported that proinflamma-tory cytokines might depress myocardial contractility.Over the past years, a series of multicenter clinical tri-als using “targeted” approaches to neutralize cytokinesin patients with heart failure have been conducted.These trials failed to show any substantial benefit inheart failure.21,22 These results raise important ques-tions about the role that cytokines play in the pathogen-esis of heart failure. Are higher levels of inflammatorymarkers part of the pathophysiological pathway leadingto cardiovascular disease or just an indirect measureof subclinical disease? If the latter is shown to be true,treatment aimed at depressing inflammation might beuseless. The increase in cytokines such as TNF-α, en-dothelin, and interleukins cannot be controlled byagents specifically blocking one or the other of thesebiological mediators. It is possible that the activationof a complex, multifaceted system like the immune-in-flammatory system (the cytokine family alone is formedof scores of different molecules), and one that certain-ly contains redundancies as do all biological systemsessential to life, cannot by modulated by blocking asingle component of the system. The system must prob-ably be manipulated more upstream or with a differentapproach. This is part of the rationale that led to thedesign of an ongoing trial in Italy, the Grupo Italianoper lo Studio della Sopravvivenza nell’Insufficienzacardiaca–Heart Failure (GISSI-HF) trial,23 to test theeffects of n-3 PUFA (polyunsaturated fatty acids) inheart failure (demonstrated to be effective in prevent-ing sudden death in the GISSI-Prevention trial24), aswell as of a statin, rosuvastatin, which, like all statins,is endowed with a powerful anti-inflammatory effect.

Other compromised organs and tissues

Focusing on clinical aspects such as anemia and renaldysfunction, considered marginal until a few years ago,has highlighted their prognostic relevance and led togreater consideration of the changes that heart failurecauses in organs and tissues other than the heart. The

alterations in skeletal muscles, liver, and lungs maybecome critical and play driving roles in the clinical evo-lution of the syndrome.

For example, anemia, common in patients with ad-vanced heart failure,25,26 can be due to occult bleedingfrom a damaged gastrointestinal tract and/or to the useof drugs, including antiplatelet agents and anticoagu-lants—which, for some reason or another, about 80%of patients with heart failure take—but can also be dueto inhibition of the production of erythropoietin andits action on the bone marrow (mainly through cyto-kines). A 1-point reduction in hematocrit in patientswith marked anemia increases the probability of deathby 15%.27 It seems that treatment with erythropoietinand substances necessary for erythrocyte production,such as iron, can be effective.28 Methodologically ap-propriate trials are currently verifying this hypothesis.

Renal dysfunction is also a relevant prognostic factorin heart failure.29-31 The observation that renal failuredoes not develop in all patients with advanced heartfailure is interesting. Heart failure can unmask renaldysfunction in patients with structural alterations and/orfunctional changes, which are often an associated ef-fect of the disease that has caused the heart failure.Thus, an increase in creatinemia is a sign of both theseverity of the heart failure and of the pathogenic pen-etration of the underlying disease. The kidney is in-creasingly becoming a therapeutic target in heart failure.There are solid data demonstrating that modulatingthe RAAS is effective in controlling the renal dysfunc-tion of heart failure. Among diabetic subjects, ACEinhibitors in insulin-dependent patients and ARBs innon–insulin-dependent patients have been shown tobe particularly effective in preventing renal damage.Data also confirm the good tolerance of β-blockers inheart failure patients with renal dysfunction. Trials areunder way to evaluate the clinical efficacy of drugsblocking the receptors of vasopressin, adenosine, andother molecules acting on the kidney.

ACUTE HEART FAILURE

Acute heart failure has long been banished to the side-lines by the international cardiological community. TheEuropean Society of Cardiology has finally producedthe first, long overdue, guidelines on acute heart fail-ure.32 The growing awareness of the relevance of thisclinical problem (which has led among other things toa greater willingness on the part of scientific journalsto publish articles dealing with this topic), more atten-tion to methodology (not least by regulatory bodies),



213

and above all the increasing investment in this fieldby some companies, should facilitate a rapid increasein knowledge and more rational and diversified thera-peutic approaches. Currently, the drug most frequentlyused (as infusion) in acute heart failure is dobutamine,a drug many consider more harmful than useful in termsof survival and which has been given a 2B recommen-dation in the European guidelines. This gives an ideaof just how rudimentary our management of acuteheart failure is.

THE ERA OF DEVICES

Electrical devices

As mentioned, simultaneous electrical stimulation ofthe two ventricles can overcome interventricular desyn-chronization, and stimulation of the left ventricle, usu-ally applied to the posterolateral wall (with a catheterplaced in the coronary sinus), can reduce intraventricu-lar desynchronization by modifying the ventricular excitation-contraction sequence. In some randomizedtrials, this therapy has improved symptoms and exer-cise capacity, reduced ventricular volumes and mitralregurgitation, improved ventricular systolic function,and reduced morbidity.33,34 There are promising, thoughnot definitive, data on its effect on mortality.35

Resynchronization therapy has been used in patientsin NYHA classes III-IV with electrocardiographic evi-dence of desynchronization (usually diagnosed fromthe presence of an intraventricular conduction delay,QRS >130 ms) and with severe ventricular systolic dys-function (LVEF <40%). It has been reported that about30% of patients receiving biventricular stimulation de-rive no benefit from the treatment.36 The identificationof candidates for this therapy is, therefore, very impor-tant and is still being defined.

As mentioned above, only one randomized study onthe use of implantable cardioverter defibrillators (ICDs)has been carried out to date specifically in patientswith heart failure, the still unpublished SCD-HeFT trial.Other controlled studies have not specifically lookedat the efficacy of ICDs in patients with heart failure.Nevertheless, in some of these studies, a considerableproportion of the enrolled population did have signsor symptoms of heart failure in addition to advancedleft ventricular systolic dysfunction.4,37,38 There is thussubstantial experience confirming that therapy withICD improves the survival and need for new hospitaladmissions in patients who have survived a heart attackor who have sustained poorly tolerated ventricular

tachycardia. The greatest benefit is seen among pa-tients with advanced heart disease and multiple riskfactors, eg, a long QRS in addition to a low EF.37

The future of devices

Preclinical and clinical evaluations of numerous me-chanical devices to control left ventricular dilation areunder way. These devices can be applied to the exteriorof the heart or placed within the left ventricle. Continu-ous refinements are being made to devices supportingleft ventricular or biventricular mechanical function asa bridge to transplantation or as destination therapy inpatients with end-stage heart failure. Newer-generationmodels are less bulky, more easily managed, less proneto infections, made of more resistant materials, andless likely to cause thrombotic complications. The ar-tificial mechanical heart, although still in an embryonicstage of clinical experimentation, has taken its firststeps along the path that should lead to greater appli-cability and acceptability within a reasonable periodof time. Electrical current suppliers are being studied;these could potentiate mechanical efficacy when ap-plied to ventricular myocardium or modulate the activ-ity of the nervous system to produce an antiarrhythmiceffect when applied to appropriate neural sites.

Diagnostic and monitoring devices are also being de-signed. These range from the small implantable elec-trocardiographic monitoring instruments already incurrent use for diagnostic purposes, to functions con-nected with pacemakers and ICDs that allow continu-ous real-time measurements of various biological pa-rameters such as heart rate, heart rate variability, stateof hydration and thus pulmonary congestion, somecharacteristics of cardiac or pulmonary blood flow ex-pressing the mechanical function of the heart, the pa-tient’s motor activity, and other variables of clinicalinterest. The dramatic acceleration in the refinementand miniaturization of computer technology and theproduction of new materials is opening up many verypromising avenues for patients with heart failure.

NEXT TARGET: PREVENTION

Secondary heart failure

Until a few years ago the epidemiological data on heartfailure, in particular concerning hospital admissionsfor, or with accompanying, heart failure were increasingat an astonishing rate, about 50% in the decade 1990-2000 in several countries (though incidence did notseem to increase similarly39). However, more recent



214

data suggest that the spread of the heart failure epi-demic seems to have been halted.40 It is possible thatpart of the increase recorded in the last few decades isartificial, linked to changes in coding systems, greaterdiagnostic attention (which could have increased sensi-tivity to the problem, though perhaps not the accuracyof diagnosis), and changes in doctors’ behaviors withgreater use of hospital admissions. However, it seemscertain that the increased prevalence of heart failureis for the most part real. The possible causes of thisphenomenon have been repeatedly analyzed, and it ismore interesting to determine why the trend seems tohave now halted, at least in the Western world. Is treat-ment, and above all prevention, managing to have anepidemiologically measurable impact on public health?This is probably the case. The decrease in hospital ad-missions seen in numerous trials with various drugsand the growing, though still only partial, adhesion toguidelines, make the recently noted evolution in theclinical epidemiology of heart failure plausible. In par-ticular, it is suggested by the decreased incidence ofheart failure in hypertensive subjects treated with var-ious drugs,41,42 in patients with ischemic heart diseasewith or without ventricular systolic dysfunction treatedwith ACE inhibitors,15 with ARBs,43 or with carvedilol,44

in subjects at high risk of atherosclerotic events, butwho do not necessarily have heart disease and whoare treated with ACE inhibitors,14 and in subjects withrenal dysfunction treated with ARBs.45 These data, to-gether with the reduction in the incidence of diabetesand atrial fibrillation observed in some trials testingboth ACE inhibitors46 and ARBs,47 indicate that besidesintervening favorably on the progression of ventriculardysfunction to decompensation and on the clinical evo-lution of the heart failure, we can also reduce the in-cidence of risk factors for heart failure, thus correctingthe roots of the chain of events that eventually culmi-nate in cardiac insufficiency. In fact, given that heartfailure is a clinical phenotype shared by the majorityof cardiovascular diseases in their late natural history,primary prevention and treatment imply prevention ofthe underlying disease. We will only be able to ensurea substantial reduction in the clinical and social di-mensions of heart failure if we are able to better con-trol systemic hypertension, ischemic heart disease,and diabetes.

Familial cardiomyopathies

Dilated cardiomyopathy The development and exploitation of knowledge on themolecular genetics of familial dilated cardiomyopathy(DCM) has taken more time than expected a decade

ago. This is due to the complexity of the matter, andprobably also depends on: (i) the phenotype (whichlooks similar in the majority of cases of DCM); (ii) fam-ilies and the potential role of endocrine, infectious, andsystemic factors that may have either a genetic basisor predisposing roles; and (iii) the absence of clearphenotypic markers that may address screening to like-ly genes/loci. In this complex field, the high costs ofscreening serial populations of patients, the lack of highthroughput tools, and the fact that the clinical benefitsare still unclear, all severely limit the translation ofknowledge from bench to bedside. Centralized geno-type studies enable the prevalence of genotypes to bedetermined, but provide practical clinical benefits onlyto a very limited number of patients and families.48,49

Clinical genetics, relying on family pedigrees and stud-ies, have shown that familial DCM is a genetically het-erogeneous disease, inherited as an autosomal domi-nant trait in the vast majority of cases. Recessive formsare rare, and difficult to prove, unless the parents ofaffected siblings are consanguineous, or more genera-tions of living family members are tested. X-linkedcardiomyopathies affecting males include dystrophin-related cardiomyopathies, Barth Syndrome, X-linkedinfantile spongiform cardiomyopathy (the latter twoare caused by a defect of the gene encoding tafazzins),and Emery-Dreyfus DCM.50,51 Mitochondrial DNA mu-tations are found in a limited proportion of DCM pa-tients when serial screening is performed in consecutivepatients (about 3%).52 Genetic testing is restricted tothe gene defect that causes the disease in the proband.In the majority of familial DCM, however, the geneticdefect remains undetected because although the knownnumber of disease genes is high, the proportion ofgenotyped patients is still low. The genes that havebeen found to recur in familial DCM include LMNA53

and dystrophin in males,54 and mitochondrial DNA.55

The majority of all other disease-genes have been exceptionally found to be mutated in familial DCM(ACTC and desmin) and serial family screening hasexcluded the recurrence of mutations in patients withDCM.56 The few exceptions of familial DCM with asso-ciated cardiac or noncardiac markers (eg, atrioventricu-lar-block in LMNA defect–associated familial DCM,increase in serum creatine phosphokinase (CPK) bloodlevels in X-linked cardiomyopathies, or hearing lossand other noncardiac phenotypes that may recur in mi-tochondrial DNA defects) have proven to be more suc-cessful than the less specific isolated idiopathic DCM.A large number of linkage studies have identified fur-ther disease loci that have never been confirmed, andno disease gene has been mapped in these loci.57



215

A novel source of knowledge and potential area of in-tervention in gene-related cardiomyopathies is emerg-ing from the strategy of screening relatives of probandswith familial cardiomyopathies.58 The studies are pro-viding evidence that 6% to 10% of relatives of patientswith familial DCM are affected, though still asymp-tomatic. Screening is based on clinical, electrocardio-graphic, and echocardiographic evaluation of all in-formed relatives who agree to the evaluation. Bloodtesting includes measurement of serum CPK.59

The benefits of these studies include presymptomaticdiagnosis and identification of instrumental noninva-sive markers that may predict the development of thedisease, and whose role should be assessed in largeclinical series. These markers include abnormal leftventricular diastolic dimension, systolic fractional short-ening, left bundle branch block, and atrioventriculardelay or block. When identified in healthy relatives ofprobands, these markers should be monitored in re-screening studies.60 Preliminary data show that an in-crease in end-diastolic dimension is a promising mark-er that predicts the development of DCM in about 30%of cases. In our experience, at an average follow-up of 32 months from the first screening, only 2% of rela-tives who were healthy at the first screening turnedout to be fully affected: their echocardiographic dataat the first screening were either normal or abnormal.An intriguing observation in our series was that a num-ber of subjects who had abnormal echocardiographicparameters at the first screening had normalized at re-screening. Therefore, additional efforts should be car-ried out to validate the role of instrumental preclinicalmarkers: tissue Doppler echocardiography is a prom-ising tool. While waiting for large clinical series to be-come available for genotype-phenotype correlation, asearch for clinical markers should be implemented. A further benefit of clinical screening and rescreeningstudies is of course the prospect of early treatment;however, whether early treatment modifies the naturalhistory of the disease is unknown. Clinical monitoringmay prevent sudden life-threatening events, help tointroduce drugs, and encourage lifestyle modification.

Hypertrophic cardiomyopathyHypertrophic cardiomyopathy (HCM) is an instructivemodel for heart failure investigation as it is a mono-factorial model of diastolic heart failure. In about 10%of cases, it evolves toward DCM, thus mimicking thatdisease. The proportion of HCM with dilated evolutionis low, but the number of patients with HCM is high:1:500 is the estimated prevalence of the disease by theage of 30 to 40 years.61,62 Therefore, of the 2000 patients

per million subjects expected to be affected, 200 willevolve to dilation and heart failure. This means thatthe clinical importance of HCM is high given that themajority of HCMs are familial (70%), inherited as au-tosomal dominant traits, with 50% of relatives expectedto be affected and possibly develop the disease. Morethan 10 disease-genes are known to cause the pheno-type: three have a particularly high frequency (MYBPC3,beta-MHC, TNNT2: up to 60% of cases), while muta-tions of the remaining genes are rare. Genotype-phe-notype correlation studies have provided preliminaryevidence that HCM caused by beta-MHC (beta–myosinheavy chain) defects is associated with more severehypertrophy, higher arrhythmogenic risk, and higherand earlier penetrance than that caused ie, by MYBPC3gene defects, and that TNNT2 defects cause a mildhypertrophic phenotype with high arrhythmogenic risk.These observations need confirmation on large consec-utive series of patients. There are no studies address-ing the risk of evolution to heart failure. The molecularbasis of penetrance complications is far from eluci-dated. Modifier genes are probably involved, complexgenotypes (double or compound heterozygosity) couldexplain this inheritance complication. To further in-crease the complexity of the clinical translation frombench to bedside of the molecular genetics of HCM,hypertrophy may be absent: this is a paradox support-ed by the documentation of genetically affected, butphenotypically healthy, family members, especially inTNNT2 defect carriers.63 Genotypically affected sub-jects are at risk of sudden death independently of thephenotype.

Besides molecular genetic analysis, clinical screeningis a key strategy of prevention in HCM. The low, incom-plete, and variable penetrance (a nonpenetrant phe-notype in a parent of an affected son with an affecteduncle is the typical example) is a complication thatdoes not limit the value of clinical family screening. Thescreening identifies affected asymptomatic relativesof the proband, and provides the basis for early treat-ment and arrhythmogenic risk stratification. Whetherearly β-blockade may modify the natural history ofthe disease is still unknown. The majority of the pastefforts have sought to identify disease-genes, collectlarge, informative families for linkage, and start geno-typing of series of patients. The majority of these stud-ies do not inform on the true prevalence of genotypesin the whole HCM patient population, since they havebeen performed in nonconsecutive series represent-ing the sum of the historical collections of the largefamilies in which disease genes have been mapped. The genotype is clinically relevant: if the disease-gene



216

mutations are the sole cause of the disease then theiridentification implies that, sometime during the courseof their life (unless the penetrance limits or abatesthe expectancies at an unknown rate) the mutation car-riers will develop the disease. What room is there forprevention, and what is its target: arrhythmias or heartfailure? The strategy of screening relatives of probandsis equally or even more useful than in familial DCM:HCM may be symptom-free during its entire naturalhistory, or may cause life-threatening arrhythmias atfirst onset.

“Pure restrictive” cardiomyopathy phenotypeAs for the most rare form of cardiomyopathy—the “purerestrictive” cardiomyopathy (RCM) phenotype—newtargets for prevention should rely on knowledge that isnow available.64 Restrictive phenotypes include primaryRCM, both isolated and associated with atrioventricu-lar block or with myopathy or with systemic diseasessuch as amyloidosis. The only known disease genesassociated with RCM are desmin (autosomal dominantin the majority of cases, causing desmin accumulationwith atrioventricular block65,66) and αB-crystallin,67

which causes a phenotype similar to that of desminaccumulation, but with associated cataract. The natu-ral history of these diseases evolves, over a variablerange of time, to end-stage heart failure, and at pres-ent there is nothing that can be done about prevention.Remaining RCMs are orphan diseases that still needto be assigned to specific disease genes.

In the RCM setting, the most frequent and likely causeis amyloidosis. Identification of amyloidogenic proteinconditions therapeutic decision-making. ApoA1 amy-loid RCM can be transplanted with low risk of recur-rence. Transthyretin (TTR) amyloid RCM requires heartand liver transplantation. Primary amyloid RCM, witheither κ or λ chains, can be either pharmacologicallytreated, when the diagnosis is early, or transplantedwith combined marrow or stem cell transplantation.Serum amyloid A (SAA) amyloidosis requires treatmentof the underlying inflammatory or autoimmune disease,and β2-microglobulin amyloidosis does not affect theheart.68 Therefore, in the setting of RCM there is a lotthat can be done.

In summary, new targets of prevention in cardiomyo-pathies should concern mostly early and preclinicaldiagnosis and rely on cardiological instruments suchas screening and rescreening as well as on moleculargenetics—this, however, is costly, time-consuming,and still limited to less than 1% of the European pop-ulation.

LOOKING TOWARD THE FUTURE

Every single biological process of the body is controlledby the expression of largely unknown genes and genet-ic programs. Comparative embryology has identifiedsome forms of congenital heart disease as the expres-sion of genetic programs characteristic of ontogeneti-cally more primitive animal species (such as amphib-ians, reptiles, etc). We know that greater or lesserexpression of key enzyme activities following stimulisuch as cellular stretching can direct the cardiomyo-cytes toward hypertrophy or apoptosis. Genetic analy-ses carried out on biopsy samples of human myocar-dium taken during application of ventricular mechanicalassistance in patients with end-stage heart failureand on the same hearts explanted during heart trans-plant operations have shown that gene expression isradically different depending on the ischemic or non-ischemic etiology of the heart disease, and equallydramatic changes are induced by prolonged unload-ing following mechanical assistance.48 Many other ex-amples could be mentioned.

Every therapeutic intervention involves biological se-quences governed by genes that the therapy directlyor indirectly activates or inhibits. Therapeutic researchis moving, albeit tentatively, in this direction. It is nowconceivable that we could, thanks to current technol-ogy, obtain cells capable of producing mediators thatwould be more useful, with fewer undesirable effectsin given pathological conditions, or engineered in sucha way as to produce new molecules, such as the “au-tologous drugs,” or “supercontractile” myocytes, etc. The ability to mitigate myocardial hypertrophy by direct-ly influencing the natural responses of the myocytesto a given workload level, initiation of apoptotic mech-anisms, and activation of cell repair mechanisms couldbecome feasible therapeutic pathways. One concreteexample is the last aforementioned mechanism: a re-pair approach to cardiological therapy rather than amodulatory or replacement approach.

One of the most important recent breakthroughs inmedicine is the prospect of using the regenerativepotential of the human body for therapeutic purpos-es. Obviously, this is of particular interest in chronicdiseases characterized by a progressive decline in thestructure and function of organs or tissues that theavailable therapy is unable to stop. Various workinghypotheses were offered in a recent review in theLancet, the essential points of which are discussedbelow.49



217

Reactivation of postmitotic cardiomyocyte replication

The genetic program for reinitiating DNA synthesisexists in cardiomyocytes, but there is also a programthat protects against uncontrolled proliferation ofcontracting cardiomyocytes, which is probably relatedto continuous active suppression of cell-cycling activity(or to an absence of expression of cell-cycle promotingfactors). Cell-cycling can be reinitiated by overexpress-ing cell-cycle promoting factors, but this seems tolead to immediate cardiomyocyte apoptosis. The pos-sibility of reactivating safe cell-cycling and whether thisprocess would be sufficient to meet clinical needs isuncharted territory.

Cloning of artificial organs

The lack of natural organs available for transplantationis a well-known fact, and there is no reason to anticipateany significant increase in organ supply in the future.In contrast, an increased demand for transplantableorgans is very likely. Therapeutic cloning might meetthis need. The most obvious way would be to inject anucleus taken by a skin biopsy into an enucleated donoroocyte, then to modulate the multiplication and dif-ferentiation of the resulting cells into cardiomyocytes.These clone cardiomyocytes would then be reinjectedas such or used in conjunction with a biodegradablescaffold to generate an artificial heart. This process istheoretically feasible, but there is no evidence so farthat it really works. Moreover, the use of embryoniccells is still matter of strong debate.

Organ regeneration via stem cells

There are strong data to suggest that autologous pro-genitor cells can home to myocardial tissue and differ-entiate into myocytes, smooth muscle cells, or endothe-lial cells. The autologous cells may be mononuclearbone narrow cells or, alternatively, muscle satellite cells.

Clinical experience in this field is promising, and fur-ther clinical research is ongoing. Satellite cells, ableto proliferate and become committed to the myocytelineage when stressed by workload, have recentlybeen reported to be present in the human myocardi-um. If this is confirmed and the number of such localpluripotent cells is sufficient to generate a clinicallysignificant regenerative process, a new method of en-dogenous myocardial repair would be available. Theauthors of the Lancet review, acknowledging that manyfundamental questions are still open, suggested both“healthy skepticism” and “cautious optimism.”49 Thisis an honest position worthy of being shared. However,sooner or later, cell therapy for heart failure will cometo stay.

IN THE MEANTIME, THE ROLE OF DISEASE MANAGEMENT

AND COMMON SENSE

In daily practice, it is abundantly clear to the cardiolo-gist and hospital internist that the continuous flow ofhospital admissions of patients with heart failure ispartly due to the limited efficacy of available therapies,and to their suboptimal use, but above all to a rigidlycompartmentalized care system that imposes a stran-glehold on hospital and community doctors, as well asto the lack of patient education and assistance in thecommunity. There are no population studies on thissubject, but very encouraging, reasonably sized, ran-domized studies exist.69-74 The difficulty lies mainly inhaving to coordinate the often conflicting priorities ofdoctors/specialists and health care authorities. Thelatter are obsessed with economic problems and moreintent on ensuring immediate control of expenses thanon achieving long-term public health care programgoals. In other words, although we know (more or less)what to do, we are unable to organize ourselves accord-ingly. However, we must not give up, because so manyof the health care issues of patients with heart failuredepend, at least for the present, on our success.



218

REFERENCES

1. Packer M.

The neurohormonal hypothesis. A theory to explain the mechanismof disease progression in heart failure.

J Am Coll Cardiol. 1992;20:248.

2. Swedberg K, Kjekshus J, Snapinn S.

Long-term survival in severe heart failure in patients treated withenalapril: ten years follow-up of CONSENSUS I.

Eur Heart J. 1999;20:136-139.

3. Jong P, Yusuf S, Rousseau MF.

Effect of enalapril on 12-year survival and life expectancy inpa-tients with left ventricular systolic dysfunction: a follow-up study.

Lancet. 2003;361:1843-1848.

4. Kadish A, Dyer A, Daubert J, et al.

Prophylactic defibrillator implantation in patients with nonischemicdilated cardiomyopathy.

N Engl J Med. 2004;350:2151-2158.

5. Salukhe T, Dimopoulos K, Sutton R, et al.

Life-years gained from defibrillator implantation. Markedly non-linear increase during 3 years of follow-up and its implications.

Circulation. 2004;109:1848-1853.

6. European Society of Cardiology.

Guidelines on diagnosis and treatment of chronic heart failure—European Society of Cardiology.

Eur Heart J. To be published.

7. Bouvy ML, Heerdink ER, Leufkens HGM, et al.

Predicting mortality in patients with heart failure: pragmatic approach.

Heart. 2003;89:1255-1264.

8. Whang W, Mittleman M, Rich DQ, et al.

Heart failure and the risks of shocks in patients with implantablecardioverter defibrillators. Results from the triggers of ventriculararrhythmias (TOVA) study.

Circulation. 2004;109:1368-1391.

9. Follath F, Cleland JGF, Just H, et al.

Efficacy and safety of intravenous levosimendan compared withdobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.

Lancet. 2002;360:196-202.

10. Moiseyev VS, Poder P, Andrejevs N, et al.

Safety and efficacy of a novel calcium sensitizer, levosimendan, inpatients with left ventricular failure due to an acute myocardialinfarction. A randomised, placebo-controlled, double-blind study(RUSSLAN).

Eur Heart J. 2002;23:1422-1432.



219

THREE KEY QUESTIONS

Heart failure therapy is an area of constant changepar excellence: change made unavoidable in orderto keep pace with the increasingly numerous andcomplex pathophysiological mechanisms involvedin heart failure that have been discovered over thepast 30 years. Probably one of the most enlighten-ing insights is the current understanding of heartfailure as the ultimate common outcome of an im-pressive array of disorders and diseases. To date,three main models have been successively de-scribed to explain the causes and consequences ofpump failure: (i) pump failure causing decreasedrenal blood flow and fluid retention; (ii) pump fail-ure causing diffuse vasoconstriction, restricting theblood flow and resulting in increased cardiac workand peripheral target organ dysfunction; and (iii)the latest player in the field: pump failure caused byhyperactivity of the neurohormonal regulatory sys-tems. This pathophysiological complexity is natu-rally mirrored by the similar complexity of the ther-apeutic range of medicines, devices, and interven-tions available, the most drastic and bold of whichis, of course, the old-for-new swap—transplanta-tion. In the following section, our Experts identifythree of the fastest-moving aspects of heart failuretherapy. CRT (cardiac resynchronization therapy) isan increasingly popular method for treating ventric-ular dyssynchrony. Many devices and techniqueshave already been developed and used, promptingAngelo Auricchio and Cecilia Fantoni to ask: “Car-diac resynchronization therapy in heart failure:which type and for whom?” The answer to neuro-hormonal hyperactivity is, logically enough, neuro-hormonal modulation. Michal Komajda takes stockof the therapeutic offer and asks: “Multiple hor-monal modulation: what are the most effectivecombinations?” So successful did neurohormon-al modulation prove to be that the catchword wassoon “the more, the better.” That this is not the case,and why, inspires a question by Helmut Drexler andKai C. Wollert: “Why are we unable to complete-ly control the activation of neurohormonal sys-tems in chronic heart failure—and should we?”Much still remains to be done to gain an ever-deep-er understanding of the mechanisms leading to andarising from heart failure, and to make new thera-peutic discoveries. Just as important, however, isputting to more effective and economically sounduse what is already available, as Luigi Tavazzi con-cludes in the Lead article.



220

11. Yusuf S, Pferrer M, Swedberg M, et al.

Effect of candesartan in patients with chronic heart failure and preserved left-ventricular ejection: the CHARM-Preserved Trial.

Lancet. 2003;362:777-781.

12. Brancaccio M, Fratta L, Notte A, et al.

Melusin, a muscle-specific integrin �1-interacting protein, is requiredto prevent cardiac failure in response to chronic pressure overload.

Nat Med. 2003;9:68-75.

13. A report of the American College of Cardiology/American Heart Association Task Force on PracticeGuidelines.

ACC/AHA 2002 Guidelines update for the management of patientswith chronic stable angina.

www.acc.org; www.americanheart.org. Accessed 30 October 2004.

14. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R,Dagenais G.

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, oncardiovascular events in high-risk patients. The Heart OutcomesPrevention Evaluation Study Investigators.

N Engl J Med. 2000;342:145-153.

15. EUropean trial on Reduction of cardiac events withPerindopril in stable coronary Artery disease Investigators.

Efficacy of perindopril in reduction of cardiovascular events amongpatients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA trial).

Lancet. 2003;362:782-788.

16. Pepine CJ, Rouleau JL, Annis K, et al.

Effects of angiotensin-converting enzyme inhibition on transient ischemia: the quinapril anti-ischemia and symptoms of angina reduction (QUASAR trial).

J Am Coll Cardiol. 2003;42:2049-2059.

17. Oosterga M, Voors AA, Buikema H, et al.

Angiotensin II formation in human vasculature after chronic ACE-inhibition: a prospective, randomised, placebo-controlled study.QUO VADIS Investigators.

Cardiovasc Drugs Ther. 2000;14:55-60.

18. Vasan RS, Sullivan LM, Roubenoff R, et al.

Inflammatory markers and risk of heart failure in elderly subjectswithout prior myocardial infarction: the Framingham Heart study.

Circulation. 2003;107:1486-1491.

19. Koukkunen H, Penttila K, Kempaninen A, et al.

C-reactive protein, fibrinogen, interleukin-6 and tumor necrosis fac-tor–alpha in the prognostic classification of unstable angina pectoris.

Ann Intern Med. 2001;33:37-47.

20. Cesari M, Penninx B, Newman A, et al.

Inflammatory markers and onset of cardiovascular events. Resultsfrom the health ABC study.

Circulation. 2003;108:2317-2222.

21. Deswal A, Misra A, Bozkurt B.

The role of anti-cytokine therapy in the failing heart.

Heart Fail Rev. 2001;61:143-151.

22. Mann DL, MC Murray JV, Packer M, et al.

Targeted anticytokine therapy in patients with chronic heart failure: results of the randomised etanercept worldwide evaluation(RENEWAL).

Circulation. 2004;109:1594-1602.

23. Tavazzi L, Tognoni G, Franzosi MG, et al.

Rationale and design of the GISSI heart failure trial: a large trialto assess the effects of n-3 polyunsaturated fatty acids and rosuvas-tatin in symptomatic congestive heart failure.

Eur J Heart Fail. 2004;6:222-229.

24. GISSI-Prevenzione Investigators

Dietary supplementation with n-3 polyunsaturated fatty acids andvitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.

Lancet. 1999;354:447-455.

25. Horwich TB, Fonarow GC, Hamilton MA, et al.

Anemia is associated with worse symptoms, greater impairment infunctional capacity and a significant increase in mortality in patients with advanced heart failure.

J Am Coll Cardiol. 2002;39:1780-1786.

26. Ezekowitz JA, McAlister FA, Armstrong PW.

Anemia is common in heart failure and is associated with pooroutcomes: insights from a cohort of 12 065 patients with new-onsetheart failure.

Circulation. 2003;107:223-225.

27. Mozaffarian D, Nye R, Levy WC.

Anemia predicts mortality in severe heart failure: the prospectiverandomized amlodipine survival evaluation (PRAISE).

J Am Coll Cardiol. 2003;41:1933-1939.

28. Silverberg DS, Wexler D, Sheps D, et al.

The effect of correction of mild anemia in severe, resistant congestiveheart failure using subcutaneous erythropoietin and intravenousiron: a randomized controlled study.

J Am Coll Cardiol. 2001;37:1775-1780.

29. Nohria A, Tsang SW, Fang JC, et al.

Clinical assessment identifies hemodynamic profiles that predictoutcomes in patients admitted with heart failure.

J Am Coll Cardiol. 2003;41:1797-1804.

30. Dries DL, Exner DV, Domanski MJ, et al.

The prognostic implications of renal insufficiency in asymptompaticand symptomatic patients with left ventricular systolic dysfunction.

J Am Coll Cardiol. 2000;102:681-689.



221

31. Kearney MT, Fox K, Lee AJ, et al.

Predicting death due to progressive heart failure in patients withmild to moderate chronic heart failure.

J Am Coll Cardiol. 2002;40:1801-1808.

32. European Society of Cardiology.

Guidelines on Acute Heart Failure Therapy.

Eur Heart J. To be published.

33. Young JB, Abraham WT, Smith AL, et al.

Combined cardiac resynchronization and implantable cardioversion de-fibrillation in advanced chronic heart failure: the MIRACLE ICD trial.

JAMA. 2003;289:2685-2694.

34. Duncan A, Wait D, Gibson D, et al.

Left ventricular remodelling and haemodynamic effects of multisitebiventricular pacing in patients with left ventricualar systolic dys-function and activation disturbances in sinus rhythm: sub-study ofthe MUSTIC trial.

Eur Heart J. 2003;24:430-431.

35. Bristow MR, Saxon LA, Boehmer J, et al.

Cardiac-resynchronization therapy with or without an implantabledefibrillator in advanced chronic heart failure.

N Engl J Med. 2004;350:2140-2150.

36. Breithardt OA, Claus P, Sutherland GR.

Do we understand who benefits from resynchronisation therapy?

Eur Heart J. 2004;25:535-536.

37. Moss AJ, Zareba W, Hall WJ, et al.

Prophylactic implantation of a defibrillator in patients with myo-cardial infarction and reduced ejection fraction.

N Engl J Med. 2002;346;877-883.

38. The Antiarrhythmics versus Implantable Defibrillators(AVID) Investigators.

A comparison of antiarrhythmic-drug therapy with implantable defibril-lators in patients resuscitated from near-fatal ventricular arrhythmias.

N Engl J Med. 1997;337:1576-1583.

39. Levy D, Kenchaina S, Larson M, et al.

Long-term trends in the incidence of and survival with heart failure.

N Engl J Med. 2002;18;1397-1402.

40. Schaufberg M, Swedberg K, Köster M, et al.

Decreasing one-year mortality and hospitalization rates for heartfailure in Sweden: data from the Swedish Hospital DischargeRegistry 1988 to 2000.

Eur Heart J. 2004;25:300-307.

41. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.

Major outcomes in high-risk hypertensive patients randomised toangiotensin–converting enzyme inhibitor or calcium channelblocker vs diuretic (Antihypertensive and Lipid-Lowering treatmentto prevent Heart Attack Trial).

JAMA. 2002;288:2981-2997.

42. Staessen JA, Fagard R, Thijs L, et al.

Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. (SYST-EUR trial).

Lancet. 1997;350:757-764.

43. Dahlöf B, Devereux RB, Kjeldsen SE, et al.

Cardiovascular morbidity and mortality in the Losartan InterventionFor Endpoint reduction in hypertension study (LIFE): a randomisedtrial against atenolol.

Lancet. 2002;359:995-1003.

44. Bigger TJ, for the Coronary Artery Bypass GraftPatch Trial Investigators.

Prophylactic use of implanted cardiac defibrillators in patients athigh risk for ventricular arrhythmias after coronary–artery bypassgraft surgery. CAPRICORN trial.

N Engl J Med. 1997;337:1569-1575.

45. Brenner BM, Cooper M, De Zeeuw D, et al.

Effects of losartan on renal and cardiovascular outcomes in patientswith type 2 diabetes and nephropathy. (RENAAL trial).

N Engl J Med. 2001;345:861-869.

46. Pfeffer MA, Mc Murray JV, Velasquez EJ, et al.

Valsartan, captopril, or both in myocardial infarction complicated byheart failure, left ventricular dysfunction, or both (VALIANT trial).

N Engl J Med. 2003;349:1893-1906.

47. Cohn JN, Tognoni G, for the Valsartan Heart FailureTrial investigators.

A randomised trial of the angiotensin-receptor blocker valsartan inchronic heart failure.

N Engl J Med. 2001;345:1667-1675.

48. Blaxal BC, Tschannen-Moran BM, Milano CA.

Differential gene expression and genomic patient stratification following left ventricular assist device support.

J Am Coll Cardiol. 2003;41:1096-1106.

49. Von Harsdorf R, Poole-Wilson P, Dietz R.

Regenerative capacity of the myocardium: implications for treat-ment of heart failure.

Lancet. 2004;363:1306-1313

50. Arbustini E, Morbini P, Pilotto A, et al.

Familial dilated cardiomyopathy: from clinical presentation tomolecular genetics.

Eur Heart J. 2000;21:1825-1832.

51. Arbustini E, Morbini P, Pilotto A, et al.

Genetics of idiopathic dilated cardiomyopathy.

Herz. 2000;25:156-160.

52. Arbustini E, Diegoli M, Fasani R, et al.

Mitochondrial DNA mutations and mitochondrial abnormalities indilated cardiomyopathy.

Am J Pathol. 1998;153:1501-1510.

53. Pasotti M, Repetto A, Pisani A, et al.

Diseases associated with lamin A/C gene defects: what the clinicalcardiologist ought to know.

Ital Heart J Suppl. 2004;5:98-111.

54. Arbustini E, Diegoli M, Morbini P, et al.

Prevalence and characteristics of dystrophin defects in adult malepatients with dilated cardiomyopathy.

J Am Coll Cardiol. 2000;35:1760-1768.

55. Gavazzi A, Repetto A, Scelsi L, et al.

Evidence-based diagnosis of familial non X-linked dilated cardio-myopathy. Prevalence, inheritance and characteristics.

Eur Heart J. 2001;22:73-81.

56. Tesson F, Sylvius N, Pilotto A, et al.

Epidemiology of desmin and cardiac actin gene mutations in aEuropean population of dilated cardiomyopathy.

Eur Heart J. 2000;21:1872-1876.

57. Keller DI, Carrier L, Schwartz K.

Genetics of familial cardiomyopathies and arrhythmias.

Swiss Med Wkly. 2002;132:401-407.

58. Mestroni L, Maisch B, McKenna WJ, et al.

Guidelines for the study of familial dilated cardiomyopathies.Collaborative Research Group of the European Human and CapitalMobility Project on Familial Dilated Cardiomyopathy.

Eur Heart J. 1999;20:93-102.

59. Baig KM, Goldman JH, Caforio ALP, et al.

Familial dilated cardiomyopathy: cardiac abnormalities are com-mon in asymptomatic relatives and may represent early disease.

J Am Coll Cardiol. 1998;31:195-201.

60. Crispell KA, Hanson EL, Coates K, et al.

Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy.

J Am Coll Cardiol. 2002;39:1503-1507.

61. Elliott P, McKenna WJ.

Hypertrophic cardiomyopathy.

Lancet. 2004;363:1881-1891.

62. Maron BJ.

Hypertrophic cardiomyopathy. A systematic review.

JAMA. 2002;287:1308-1320.

63. Maass AH, Leinwand LA.

Mechanisms of the pathogenesis of troponin T-based familial hypertrophic cardiomyopathy.

Trends Cardiovasc Med. 2003;13:232-237.

64. Franz WM, Muller OJ, Katus HA.

Cardiomyopathies: from genetics to the prospect of treatment.

Lancet. 2001;358:1627-1637.

65. Ariza A, Coll J, Fernandez-Figueras M, et al.

Desmin myopathy: a multisystem disorder involving skeletal, cardiacand smooth muscle.

Hum Path. 1995;26:1032-1037.

66. Arbustini E, Morbini P, Grasso M, et al.

Restrictive cardiomyopathy atrioventricular block and mild to sub-clinical myopathy in patients with desmin-immunoreactive materialdeposits.


67. Goldfarb LG, Vicart P, Goebel HH, et al.

Desmin myopathy.

Brain. 2004;127:723-734.

68. Arbustini E, Gavazzi A, Merlini G.

Fibril-forming proteins: the amyloidosis. New hopes for a diseasethat cardiologists must know.

Ital Heart J. 2002;3:590-597.

69. Stewart S, Marley JE, Horowitz JD.

Effects of a multidisciplinary, home-based intervention on un-planned readmission and survival among patients with chroniccongestive heart failure: a randomised controlled study.

Lancet. 1999;354:1077-1083.

70. Krumholtz HM, Amatruda J, Smith GL, et al.

Randomized trial of an education and support intervention to preventreadmission of patients with heart failure.


71. Wright SP, Walsh H, Ingley KM, et al.

Uptake of self-management strategies in a heart failure manage-ment programme.

Eur Heart J Heart Fail. 2003;5:371-380.

72. Strömberg A, Martensson J, Fridlund B, et al.

Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure.

Eur Heart J. 2003;24:1014-1023.

73. Stewart S, Blue L, Walker A, et al.

An economic analysis of specialists’ heart failure nurse manage-ment in the UK: can we afford not to implement it?

Eur Heart J. 2002;23:1369-1378.

74. Weingarten SR, Henninh JM, Badamgarav E, et al.

Interventions used in disease management programmes for patientswith chronic illness—which ones work? Meta-analysis of pub-lished reports.

BMJ. 2002;325:1-8.



222

ver the past decade, treat-ment of heart failure (HF)has markedly improved;mortality due to pump

failure and sudden death has de-clined significantly.1,2 Hospitaliza-tions for severe symptoms of HFhave also decreased after use of an-giotensin-converting enzyme (ACE)inhibitors, β-blockers, diuretics,digoxin, and most recently, spirono-lactone. However, despite bettermedical treatment, a significantnumber of patients remain symp-tomatic. Until recently, the mainstayof treatment for advanced HF waspharmacological, with very smallnumber of patients considered forheart transplantation or left ven-tricular (LV) assist devices. Whilecardiac transplantation can be anextremely effective therapy, its avail-ability is severely limited by lack ofdonor organs—and there is still theunresolved issue of tissue rejectionafter transplantation. Mechanicaldevices to augment cardiac outputare currently only suitable for short-term use and the financial cost of

these devices is likely to limit theirwidespread application. Against thisbackground, cardiac resynchroniza-tion therapy (CRT) has emerged asa promising treatment option forsome patients with HF.

MECHANICAL AND STRUCTURAL

CONSEQUENCES OF VEN-TRICULAR CONDUCTION

DISTURBANCES

A complex blend of structural, func-tional, and biological abnormalitiesis found in patients with HF anddilated cardiomyopathy of variousetiologies. Significant QRS prolon-gation is present in approximately30% of patients with HF. Electricaldelays generate abnormal atrioven-tricular timing and dyssynchronouscontraction of left, right, or bothventricles. Furthermore, prolonga-tion of atrioventricular timing delaysatrial contraction relative to theonset of ventricular systole and re-duces the efficiency of atrial systolefor ventricular filling.

Cardiac resynchronization therapy in heart failure:which type and for whom? Angelo Auricchio, MD, PhD; Cecilia Fantoni, MD

Division of Cardiology - University Hospital Magdeburg - Magdeburg - GERMANY

O

Keywords: heart failure; ventricular conductiondisturbance; left bundle branch block; cardiacresynchronization therapy; implantable cardio-verter-defibrillatorAddress for correspondence:Prof Angelo Auricchio, Division of Cardiology,University Hospital Magdeburg, Leipziger-Straße44, 39120 Magdeburg, Germany(e-mail: [email protected])



225

Cardiac resynchronization therapy(CRT) offers a new therapeutic ap-proach for patients with ventriculardyssynchrony and moderate-to-severe heart failure who have dilat-ed cardiomyopathy, regardless ofetiology, with depressed systolicfunction and a QRS ≥120 ms.Clinical trials have shown that itis safe and effective, achieving sig-nificant improvement in clinicalsymptoms, multiple measures offunctional status, and exercise ca-pacity. Furthermore, CRT has re-duced morbidity and mortality inpatients with heart failure. Con-clusive cost-effectiveness data arenot yet available. Whether or notheart failure patients should be im-planted with a CRT plus defibril-lator (CRT-D) device versus CRTalone remains debatable, althoughgrowing evidence is pointing to ex-tensive use of implantable cardio-verter defibrillators (ICDs) in thispopulation.


COMPANION COmparison of Medical therapy, Pacing And defibrillatioN In chrONic heart failure

CRT cardiac resynchronization therapy

HF heart failure

ICD implantable cardioverter defibrillator

SCD-HeFT Sudden Cardiac Death–Heart Failure Trial

TDI tissue Doppler imaging

Left bundle branch block is themost common ventricular cause ofdelay reported in patients with im-paired pump function. This conduc-tion disturbance affects cardiacmechanics by altering right-left ven-tricular systolic and diastolic timing,causing abnormal ventricular con-traction and relaxation, worsening

the underlying systolic and diastolicperformance and increasing cardiacenergy requirements. Basically, atthe beginning of the LV ventricularsystole, the region of earliest ven-tricular activation (usually the inter-ventricular septum) contracts againstminimal workload because the re-maining ventricular myocardium(usually the lateral and posterolat-eral LV region) is still in the relax-ation or in a non-activated phase(Figure 1). The regions of early ven-tricular activation waste contractionenergy as no effective intraventric-ular pressure can develop. On theother hand, the region of late ventric-ular activation and the lateral andposterolateral ventricular regions

have to contract against a preexist-ing stiffened portion of the ventricu-lar wall (the septum). This phenom-enon has been termed mechanicaldyssynchrony (Figure 1). Mechanicaldyssynchrony generates increasedwall stress with increased cardiacwork, which may contribute to my-ocyte damage and to the develop-

ment of fibrous tissue, regional hypertrophy, and regional apopto-sis.3 All these functional andstructural changes caused by leftbundle branch block may be asso-ciated with poor prognosis and in-creased morbidity.4

CARDIAC RESYNCHRONIZATION

THERAPY

CRT is a novel nonpharmacologicaloption for symptomatic patientswith HF who have wide QRS com-plexes (>120 ms) on the 12-lead sur-face electrocardiogram (ECG) andwho are refractory to medical thera-py. The aim of CRT is to improve

cardiac performance by reducing in-ter- and intraventricular mechanicaldyssynchrony, thereby reducing my-ocardial oxygen consumption. Inorder to achieve this, the regions ofthe LV that are activated latest dur-ing sinus rhythm are stimulatedearly by delivery of a pacing stimu-lus, usually simultaneously with the

right ventricle (RV) via a separatepacing lead, thus reducing the totalactivation time for the ventricles. Inpatients with sinus rhythm, the pace-maker system will sense the atrialelectrical activation via a right atriallead and stimulate the ventricles ata programmed atrioventricular timethat is less than the intrinsic atrio-ventricular conduction time in orderto ensure full ventricular capture.

Implantation technique

The implantation technique is sim-ilar to a standard dual chamber se-quential pacemaker or implantablecardioverter defibrillator (ICD). Themost challenging aspect for achiev-


CRT in heart failure: which type and for whom? - Auricchio and Fantoni

226

Figure 1. Recording of electrical activa-tion (10-ms isochronous line) in a patientwith dilated cardiomyopathy and leftbundle branch block. The upper panelsshow electrical (left) and mechanical(pressure-volume, right) activation duringleft bundle branch block. A U-shaped ac-tivation sequence of the left ventricle (LV)is noted; the regional pressure-volumeloops show large mechanical dyssynchrony.The lower panels present the effect ofbiventricular stimulation by pacing (as-terisk) the apex of the right ventricle (notshown) and the free wall of the LV. Theelectrical activation sequence (left)shows two fronts, one coming from rightand the other from left colliding over theseptum. The pressure-volume loop (right)is now larger and shows a more homoge-neous distribution of regional strokework. The pie-shaped circle in the middleshows the 8 LV segments (lettered A to H)corresponding to the same-lettered re-gional pressure-volume recordings in the right panels.

Pre

ssure

Pre

ssure

Se

ptu

m

*

*

Volume

A

Sep

tum Lat

Ant

Post

H

D

E

B

G

C

F

Se

ptu

m

ing resynchronization therapy isplacing a permanent LV lead. Thetransvenous or thoracotomic ap-proach can be used. The transve-nous approach requires retrogradecannulation of the coronary sinus,selective angiography of the coro-nary sinus to delineate the venousanatomy (Figure 2), and final intro-duction into a coronary vein, whichlies over the epicardial surface of

the LV, of a specifically designedpacing lead. Figure 3 shows the typ-ical configuration of pacing leadsin a biventricular system implantedeither transvenously or via limitedlateral thoracotomy.

The transvenous approach may bea difficult and time-consuming tech-nique. The major limitation is thatoptions for lead placement are gov-

erned largely by the patient’s venousanatomy, which shows considerableinterindividual variability. In about10% to 15% of cases, it is not pos-sible to achieve a satisfactory LVpacing position, or left phrenic nervestimulation may occur, thus caus-ing an unpleasant sensation dueto diaphragmatic contraction.

Clinical efficacy

The beneficial effects of CRT includeimprovement in exercise toleranceand quality of life. Furthermore, CRTreduces ventricular volumes andmitral regurgitation, and improvesleft ventricular ejection fraction(Figure 4, page 228).5-7 CRT has re-cently been shown to improve mor-tality and hospitalization in a largerandomized trial.8

Most clinical trials have includedpatients with moderate or severe(New York Heart Association [NYHA]functional class III or IV) chronic HFdue to ischemic or nonischemiccardiomyopathy and widened QRS



227

Figure 2. A family of catheters for selectivecannulation of the coro-nary sinus is presentedin panel A. After can-nulation of the coronarysinus, a balloon occlu-sion using a standardSwan-Ganz catheter(panel B) is performed,followed by contrast dye injection. Panel Cshows the large variabil-ity of the coronary veins.According to the differ-ences in coronary venousanatomy, different pac-ing electrodes may beimplanted (panel D).

Figure 3. Two examples of implantation of cardiac resynchronization devices. In both cases, the atrialpacing lead and the right ventricular pacing lead are placed as in a conventional DDD pacemaker ofan implantable defibrillator. The lead for the left ventricle (arrow) may be inserted transvenously asindicated in Figure 2 or via a minimal lateral thoracotomy.

Transvenous approach Lateral thoracotomy approach

RAO 30°

➤

B

D

CAvailable in different lengths

A ➤

LAO 50°

duration on the surface electrocar-diogram. A QRS duration of 120 msor more has been the typical selec-tion threshold.9 Table I summarizesclinical criteria for patients select-ed for CRT and current clinical evi-dence supports the value of CRTfor these patients.

Few data have been collected onCRT in patients with NYHA class II,and currently this patient group isnot routinely recommended for CRT.Insufficient data are available forpatients with atrial fibrillation; al-though preliminary data supportthe efficacy of CRT in this setting,definitive data are lacking. Similarly,the question of whether heart fail-ure patients with a standard pace-maker indication for bradycardiabenefit from CRT is still unanswered.In contrast, there is increasing evi-dence that the implantation of CRTinstead of a standard single-cham-ber or dual-chamber pacemaker

may be appropriate for patientswith paroxysmal or permanent rap-idly conducting atrial fibrillationwho undergo His bundle ablation.

IDENTIFYING INDIVIDUALRESPONDERS

All randomized clinical CRT trialshave used statistical techniques to define the response of groups ofpatients to CRT. No technique isavailable to predict reliably theclinical response of a given individ-ual. The large clinical improvementobserved in some individuals afterCRT (the so called “Lazarus” effect)has created the perception that patients who do not exhibit such improvement are not respondingpositively to CRT. However, manypatients who do not show overt im-provement may nevertheless bene-fit from a less observable slowing ofdisease progression by living longerand remaining out of the hospital.Since these benefits can only bedetermined for populations, it maybe inappropriate to withhold CRTfrom patients who meet mortalityand morbidity trial indications, but



228

AHA/ACC/NASPE GuidelinesPacing recommendations

(Class IIa Indication)

• Medically refractory heart failure

• Functional New York Heart Association Class III or IV

• Idiopathic dilated or ischemic cardiomyopathy

• QRS duration ≥130 ms

• Left ventricular ejection fraction≤35%

• Left ventricular end-diastolic diameter ≥55 mm

Table I. Inclusion criteria listed in the recentlypublished AHA/ACC/NASPE guidelines forcardiac resynchronization therapy.

Abbreviations: ACC, American College ofCardiology; AHA, American Heart Association;NASPE, North American Society for Pacingand Electrophysiology.

Figure 4. Reverse remodeling in two patients implanted with a cardiac resynchronization device.

1 week after CRT 1 year after CRT 3 years after CRT

1 week before CRT 6 months after CRT 1 year after CRT

who do not have indicators predict-ing individual functional improve-ment. With this caveat, various fac-tors that may influence the clinicalimpact of CRT in individual patientsare described below.

QRS duration

Duration of the QRS complex is oneof the simplest ways to measuretiming abnormalities that may havea mechanical correlate. Indeed, allrandomized studies to date haveused this variable to select patients.Basal QRS duration has been shownto be associated with the degree ofmechanical dyssynchrony and withthe short-term clinical improvementobtained from CRT (Figure 1). Clin-ical trials have consistently shownthat in patients with QRS complex>150 ms, functional capacity, quali-ty of life, and exercise tolerance aresignificantly improved after a fewmonths of CRT. In contrast, patientswith a shorter QRS complex (120-150 ms) show less or no significantchanges in functional capacity, qual-ity of life, and exercise tolerance.10

However, preliminary evidence indi-cates that patients with shorter QRSalso may improve after CRT longerthan 6 months, suggesting a time-dependency effect of CRT based onthe baseline QRS width. The effect ofCRT on disease progression in thesetwo subgroups of patients, as evalu-ated by reverse remodeling, morbid-ity, or mortality is still unknown.However, CRT has been shown todecrease hospitalization and all-cause mortality in NYHA class III/IVpatients with QRS >120 ms.

Echocardiographic assessment

In patients with HF and ventricularconduction delay, four different lev-els of ventricular asynchrony havebeen recognized: atrioventriculardelay, interventricular and intraven-

tricular delay, and intramural delay.Some patients with HF with de-pressed LV ejection fraction despitenormal duration of the QRS complexmay present with echocardiograph-ically assessed mechanical dyssyn-chrony of similar magnitude as pa-tients with considerably prolongedQRS duration. The reasons for this“electromechanical dissociation” arenot clear, but possible explanationsinclude the relatively poor represen-tation on the surface ECG of elec-trical impulses from diseased areasof the LV and “uncoupling” of me-chanical contraction from electricalstimulation due to abnormalities ofcalcium homeostasis in cardiac my-ocytes. Although preliminary datasuggest that patients with mechan-ical dyssynchrony despite normalQRS may benefit, CRT should notbe extended to this group withoutprospective randomized studies.

With the exception of intramuraldelay, conventional or Doppler echo-cardiography allows a direct quan-tification of the degree of mechanicalasynchrony. Some of the echocar-diography-guided indices are basedon timing abnormalities of specificLV regions, others explore the me-chanics of the entire LV, and othersevaluate a difference in timing be-tween the right and left ventricles.Although pilot studies are promis-ing, the validity of these mechanicalindices of dyssynchrony to predictoutcome after CRT has not beenprospectively established. These in-dices also may not help identifyingthe patients who would benefit fromthe potential preventative effect ofCRT in stopping progression ofdyssynchrony and its associatednegative effects on cardiac function,hypertrophy, and remodeling. How-ever, measures of mechanical resyn-chronization may help optimizetherapy by determining best leadposition and proper atrioventriculardelay programming.

Mechanical abnormalitiesdetected by conventional

echocardiography

Interventricular delay time is usu-ally defined as the time differencebetween the onset of pulmonaryartery flow and the onset of aorticflow with respect to the beginningof the QRS complex. A delay >40 msis considered indicative of signifi-cant dyssynchrony. Because the timeto ejection of the RV and LV couldbe influenced by several factors, thepredictive utility of such interven-tricular delay has been questioned.Intraventricular delay is consideredthe most important one for identi-fying patients who will experiencethe largest short-term clinical re-sponses by CRT, and is defined asthe mechanical dispersion of motionof the LV. M-mode echo-imaginghas been used to determine the de-lay exclusively between the initialseptal inward motion, and posteri-or wall motion. This delay time hasbeen correlated with chronic im-provement in LV diameters afterCRT. The major limitation of thisindex is that it does not account fordelays possibly located elsewherein the LV. Heterogeneous regionalwall motion synchrony with leftbundle branch block QRS morphol-ogy has also been demonstrated by2-D echocardiography.

Mechanical abnormalitiesdetected by tissue Doppler imaging

Regional systolic and diastolic syn-chrony can be evaluated by tissueDoppler imaging (TDI) by comparingthe time to peak systolic contrac-tion and early diastolic relaxation ofmultiple segments. TDI appears tooffer a comprehensive assessmentof cardiac mechanical synchrony.Although improvement of interven-tricular dyssynchrony after CRT hasbeen demonstrated by TDI, TDI pa-



229



rameters of interventricular delayhave not been shown to predict theimprovement of cardiac function.

A number of parameters based onTDI have been proposed to evaluateintraventricular dyssynchrony. Theseparameters examine either the timeto peak myocardial systolic contrac-tion (Ts) between two or more seg-ments or the dispersion (standarddeviation) of Ts (Ts-SD) over multi-ple segments in the LV, typically 12.

A Ts-SD >33 ms has been shown tostrongly predict short-term reverseremodeling. Other proposed indicesof systolic dyssynchrony includecounting the number of segmentswith postsystolic shortening andpossibly strain rate parameters. Theformer parameter has been observedto correlate with a beneficial changein systolic function. However, a re-cent comprehensive analysis sug-gested that assessment of Ts-SD isthe best predictor of reverse remod-eling. This may be the best currentcandidate to replace QRS with anindex of mechanical dyssynchronyfor the selection of new patients inexpanded CRT trials.

PROTECTION FROM SUDDEN CARDIAC DEATH

BY IMPLANTABLE CARDIOVERTER DEFIBRILLATOR

Sudden cardiac death is a cata-strophic event, the annual incidenceof which increases from 2% to 6 %per year in patients with NYHAclass II symptoms up to 24% peryear for patients with class III to IVsymptoms.11 Ventricular tachycardiaor fibrillation is the predominantmode of death. It has been shownthat the implantable cardioverterdefibrillator (ICD) is the most pow-erful—and therefore first-line—therapeutic approach for secondaryas well as primary prevention for

sudden death. The recently conclud-ed Sudden Cardiac Death–HeartFailure Trial (SCD-HeFT), has pro-vided further evidence that ICD im-plantation in addition to the bestpharmacological therapy (includingACE inhibitors, angiotensin II type 1(AT1) receptor blockers, β-blockers,diuretics, and spironolactone) is themost effective long-term (at 5 years)therapy compared with convention-al optimal therapy alone or withamiodarone given on top of the bestmedical therapy for prolonging lifein patients with HF.

The rationale for the use of ICD inCRT devices is primarily based onthe assumption that sudden deathprevention in patients with HF willprovide mortality benefits abovethose of CRT alone. The COmpari-son of Medical therapy, Pacing AnddefibrillatioN In chrONic heart fail-ure (COMPANION) study has shownmarked reduction in combinedmeasures of morbidity and mortal-ity as well as for mortality with CRTalone and with CRT plus defibrillatortherapies (CRT-D). The morbiditydata from COMPANION indicateda near-equal 1-year benefit for bothgroups (with and without an ICD);in contrast to CRT alone, whichdemonstrated a relative risk reduc-tion in all-cause mortality of about24% (P=0.060), CRT-D provided alarger (36%) relative risk reductionin mortality compared with optimaldrug therapy (P=0.003). A reductionin all-cause mortality and hospital-ization for HF by 40% following CRTsuggests a substantial reduction inthe use of medical resources. Thesefindings are supported by other CRTtrials.12

The important issue raised by theCOMPANION study is whether allpatients with HF indicated for CRTshould be treated with an addition-al ICD. Therefore, despite the factthat the CRT-D device has larger

initial cost, and may require moreextensive follow-up than CRT alone,this strategy may be most cost-ef-fective particularly when measuredin terms of quality-adjusted life-years gained. However, longer-termdata are not available and a directcomparison between CRT and CRT-Dhas not been performed yet.

MONITORING FEATURESOF CRT DEVICES

The monitoring features of conven-tional pacemakers or ICDs mainlyfocus on device-related parame-ters such as pacing threshold, im-pedance, R-wave amplitude, andstorage of intracardiac electrograms.Careful hemodynamic control andelectrical monitoring is now imple-mented into CRT devices. Hemody-namic parameters can be either di-rectly or indirectly monitored viathe implanted devices. Specific sen-sors of the maximum pressure de-rivative are already implemented.

Furthermore, heart rate and heartrate variability can also be continu-ously monitored with an implantedCRT device. Finally, recording ofaccelerometer signals, which usu-ally reflect the patient’s physical ac-tivity, is already used in pacemakersand implantable cardioverter-defib-rillators. This is now used for mon-itoring the HF-treated patient activ-ity, as well. Initial experience withrecording of patient activity trackedby accelerometer has shown thatactivity monitored by accelerome-ters is highly sensitive and specificin detecting the patient’s physicalactivity. However, the accuracy ofmonitoring chronic hemodynamics,lung water content, heart rate, andphysical activity changes in patientswith HF has yet to be determined.It is also unknown whether majorcardiac events can be forecasted bymonitoring one or more of theseparameters.

230

SUMMARY

Cardiac resynchronization therapyis now proven to be a valuable ad-junctive treatment to standard phar-macological therapy for patientswith HF with dyssynchrony. Thistherapy has demonstrated largesymptomatic improvements as wellas a strong impact on disease pro-gression. The likelihood is that theindication for device implantationwill expand in the future, so thatpatient selection techniques needto improve to ensure that the over-whelming majority of patients re-ceiving this therapy also benefitfrom it. QRS duration remains themost practical and validated meansfor selecting patients for CRT, be-cause it is clinically simple tomeasure and widely available, andits value as a selection criterionhas been proven in large, random-ized outcome trials demonstratinga mortality and hospitalizationbenefit with CRT.

The predictive value of QRS dura-tion may derive from a close corre-lation of long QRS and a correspon-ding mechanical dyssynchrony,which increasingly is believed to bethe main substrate for CRT efficacy.Evidence that QRS duration is animperfect indicator of mechanicaldyssynchrony, added to the desireto identify individual patients likelyto experience immediate large im-provements in clinical conditionwith CRT, has led to a search for oth-er noninvasive techniques, basedmainly on imaging, that directlymeasure mechanical dyssynchrony.

However, particular indices of me-chanical dyssynchrony that bestpredict clinical improvement havenot been established, and it is un-clear whether CRT is preventing dis-ease progression in patients withprolonged QRS before severe me-chanical dyssynchrony is apparent.

At the present time, evidence-basedmedicine supports the use of pro-longed QRS (>120 ms) as an indica-tor of patients with severe HF whoshould be prescribed CRT. Nonin-vasive imaging techniques can beused to verify that resynchroniza-tion has been achieved.

REFERENCES

1. Cohn JN, Johnson G, Ziesche S,Cobb F, et al.

Comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment ofchronic congestive heart failure.

N Engl J Med. 1991;325:303-310.

2. Captopril Multicenter ResearchGroup.

A placebo-controlled trial of captopril in refractory chronic congestive heart failure.

J Am Coll Cardiol. 1983;2:755-763..

3. Auricchio A, Abraham WT.

Cardiac Resynchronization therapy: currentstate of the art. Cost versus benefit.

Circulation. 2004;109:300-307.

4. Baldasseroni S, Opasich C, GoriniM, et al, on behalf of the Italian Network on Congestive Heart FailureInvestigators.

Left bundle branch block is associated with1-year sudden and total mortality rate in5517 outpatients with congestive heart fail-ure: a report from the Italian Network onCongestive Heart Failure.

Am Heart J. 2002;143:398-405.

5. Abraham WT, Fisher WG, Smith AL,et al.

Cardiac resynchronization in chronic heartfailure.

New Engl J Med. 2002;346:1902-1905.

6. Auricchio A, Stellbrink C, Sack S,et al.

Long-term clinical effect of hemodynami-cally optimized cardiac resynchronizationtherapy in patients with heart failure andventricular conduction delay.

J Am Coll Cardiol. 2002;39:2026-2033.

7. Cazeau S, Leclercq C, Lavergne T,et al.

Effects of multisite biventricular pacing inpatients with heart failure and intraventric-ular conduction delay.

N Engl J Med. 2001;344:873-880.

8. Bristow MR, Saxon LA, Boehmer J,et al; Comparison of Medical Therapy,Pacing, and Defibrillation in HeartFailure (COMPANION) Investigators.

Cardiac resynchronization therapy with orwithout an implantable defibrillator in ad-vanced chronic heart failure.

N Engl J Med. 2004;350:2140-2150.

9. Gregoratos G, Abrams J, EpsteinAE, et al.

ACC/AHA/NASPE 2002 guideline updatefor implantation of cardiac pacemakers andantiarrhythmia devices: summary article—a report of the American College of Cardiol-ogy/American Heart Association Task Forceon Practice Guidelines (ACC/AHA/NASPECommittee to Update the 1998 PacemakerGuidelines)

Circulation. 2002;106:2145-2161. ACC—ww.acc.org, AHA—www.americanheart.org,NASPE—www.naspe.org.

10. Auricchio A, Stellbrink C, Butter C,et al.

Clinical efficacy of cardiac resynchroniza-tion therapy using left ventricular pacing inheart failure patients stratified by severityof ventricular conduction delay.

J Am Coll Cardiol. 2003;42:2109-2116.

11. MERIT-HF Study Group.

Effect of metoprolol CR/XL in chronic heartfailure. Metoprolol CR/XL Randomized In-tervention Trial in Congestive Heart Failure(MERIT-HF).

Lancet. 1999;353:2001-2007.

12. Bradley DJ, Bradley EA, Baugh-man KL, et al.

Cardiac resynchronization and death fromprogressive heart failure. A meta-analysisof randomized controlled trials.

JAMA. 2003;289:730-740.



231

232


hronic heart failure (CHF)is a major burden for healthcare systems due to itsgrowing incidence, partic-

ularly in elderly and very elderly pa-tients, and to the high mortalityand morbidity associated with thiscondition.

The concept of neurohormonal stim-ulation as a key component of theonset and progression of heart fail-ure was developed in the 1980s andproved to be a major breakthroughin the understanding and clinicalmanagement of this condition. Thebody of evidence supporting neu-rohormonal modulation as a majormedical goal in heart failure is im-mense, and is based on numerous,large, and well-conducted clinicaltrials that have enrolled more than100 000 patients exposed to vari-ous neurohormonal modulators.

Historically, this scientific period canbe divided into three distinct eras:• The demonstration of the benefi-cial effect of angiotensin-convertingenzyme (ACE) inhibitors on top ofconventional treatment, consisting indiuretics and digitalis±vasodilators.• The use of β-blockade on top ofACE inhibitors and diuretics±digi-talis.• The more recent use of other neu-rohormonal modulators, includingangiotensin II receptor antagonists(ARBs, or sartans) and aldosteroneantagonists, such as spironolactoneand eplerenone.

The aim of this review is to discussthe best neurohormonal antagonistcombinations, the order of initia-tion of these various antagonists,and to define the patient profilesfor which this medical approach ismost effective. Due to the lack ofdata in heart failure with preservedsystolic function (“diastolic” heartfailure), most of the evidence re-viewed here focuses on heart failurewith depressed systolic function.

ACE INHIBITION AND β-BLOCKADE:

THE GOLD STANDARD OF NEUROHORMONAL MODULATION IN CHF

The first trial showing a benefit ofneurohormonal modulation in se-vere heart failure was the COopera-tive North Scandinavian ENalaprilSUrvival Study (CONSENSUS), whichshowed a substantial 28% reductionin mortality in New York Heart As-sociation (NYHA) class IV CHF pa-tients.1 In 1991, two landmark trialsestablished the benefit of ACE in-hibition on top of conventionaltherapy (Studies Of Left VentricularDysfunction, SOLVD)2 or comparedwith conventional vasodilator treat-ment (Vasodilator–Heart FailureTrial II, V-HeFT II).3 In SOLVD, ACEinhibition was associated with arelative risk reduction of 16% in all-cause mortality, of 22% in heart fail-ure death, and of 26% in death orhospitalizations for heart failure inpatients with NYHA class II and III

Multiple neurohormonal modulation: what are the most effective combinations? Michel Komajda, MD, FESC

Department of Cardiology - Pitié-Salpêtrière Hospital - Paris - FRANCE

Keywords: neurohormonal modulation; chronicheart failure; treatment; ACE inhibitor; β-blocker;aldosterone antagonist; angiotensin II receptorantagonist; polypharmacy Address for correspondence:Prof Michel Komajda, Département de Cardio-logie, Hôpital Pitié-Salpêtrière, 52 bld VincentAuriol, 75654 Paris Cedex 13, France(e-mail: [email protected])


CNumerous clinical trials on neuro-hormonal modulation have shownthat angiotensin-converting enzyme(ACE) inhibition combined with�-adrenergic blockade improvesall-cause cardiovascular mortality,sudden cardiac death, and hospi-talization rate, including in patientswith depressed systolic function.International guidelines now rec-ommend dual neurohormonal in-hibition in post–myocardial infarc-tion left ventricular dysfunction andin all symptomatic patients. In patients intolerant to, or with con-traindication to, one of these com-pounds, angioten-sin II receptorblockers (ARBs) are a good alter-native. In symptomatic patients,addition of an ARB or/and aldos-terone antagonist to the ACE in-hibitor and �-blocker can improvethe outcome. Other options, such asvasopeptidase inhibitors, endothe-lin receptor antagonists, and argi-nine-vaopressin antagonists arecurrently under evaluation.

CHF. In V-HeFT II, there was an 18%reduction in mortality, and a sub-stantial number of sudden cardiacdeaths were avoided by ACE inhi-bition in comparison with a combi-nation of hydralazine and nitrates.Following these two trials, it wasfurther demonstrated that ACE in-hibitors were also beneficial in post–myocardial infarction mortality inpatients with reduced ejection frac-tion <40% (Survival And VentricularEnlargement [SAVE] trial)4 and thatthey slowed the progression of thedisease to overt heart failure anddecreased the number of relatedhospitalizations in asymptomaticleft ventricular dysfunction (SOLVD-prevention).5 These observations,followed by other confirmatory tri-als, led to the recommendation ofthe use of ACE inhibitors in a broad

spectrum of patients with left ven-tricular dysfunction, NYHA Class II,III, or IV, in the guidelines publishedby the European Society of Cardiol-ogy (ESC).6 Five ACE inhibitors arerecommended in the treatment ofCHF in these guidelines: enalapril,captopril, perindopril, lisinopril, andramipril.

The demonstration of the benefit ofβ-blockers was made in three trialspublished in 1996 and 1999 (Carve-dilol US program7; Cardiac Insuffi-ciency BIsoprolol Study II [CIBIS II]8;MEtoprolol controlled release Ran-domized Intervention Trial in HeartFailure [MERIT-HF]9). The β-block-ers carvedilol, bisoprolol, and meto-prolol succinate, given on top of acombination therapy consisting ofdiuretics, ACE inhibitors ± digitalis

and vasodilators, resulted in a sub-stantial reduction in all-cause mor-tality, heart failure hospitalizations,and/or sudden cardiac death. Theresults were so dramatic that theyled to the early termination of thethree trials. One of the most remark-able results of these trials was themagnitude of the effect observed onmortality and hospitalizations: therelative risk reduction in all-causemortality was 65% with carvediloland 34% with metoprolol and biso-prolol. Similarly, all-cause hospital-izations were reduced by 20% inCIBIS II, whereas mortality or hos-pitalization for worsening heart fail-ure was reduced by 32% in MERIT-HF. A significant 34% reduction inall-cause mortality was also demon-strated in patients with severerCHF in the CarvedilOl ProspEctiveRaNdomIzed CUmulative Survival(COPERNICUS) trial10 and of 23% inpost–myocardial infarction with leftventricular dysfunction in the CArve-dilol PostinfaRct survIval COntRolledevaluatioN (CAPRICORN) trial.11

These results were embodied in theESC guidelines, which recommendthe use of dual neurohormonal in-hibition in all stable NYHA class II,III and IV patients, together with di-uretics (Class IA recommendation).This regimen is also recommendedin patients with post–myocardialinfarction with left ventricular dys-function (Class IB recommenda-tion). Thus, there is no longer anycontroversy on the need for dualneurohormonal therapy using ACEinhibitors and β-blockers in CHF.

IS DUAL NEUHORMONALINHIBITION USED

IN PRACTICE?

A number of surveys have been car-ried out, both at national and inter-national levels, to determine to whatextent CHF guidelines are imple-mented in daily practice. All these

233


Multiple neurohormonal modulation: what are the most effective combinations? - Komajda


ARB angiotensin receptor blocker

AT1 angiotensin II type 1 receptor

CAPRICORN CArvedilol PostinfaRct survIval COntRolled evaluatioN

CHARM Candesartan in Heart failure Assessment of Reductionin Mortality

CHF chronic heart failure

CIBIS II Cardiac Insufficiency BIsoprolol Study II

CONSENSUS COoperative North Scandinavian ENalapril SUrvival Study

COPERNICUS CarvedilOl ProspEctive RaNdomIzed CUmulative Survival

ELITE II Evaluation of Losartan In The Elderly II

EPHESUS Eplerenone Post-AMI Heart failure Efficacy and SUrvival Study

MERIT-HF MEtoprolol controlled release Randomized Interven-tion Trial in Heart Failure

OPTIMAAL OPtimal Trial In Myocardial infarction with Angio- tensin II Antagonist Losartan

RALES Randomized ALdactone Evaluation Study

RAS renin-angiotensin system

SAVE Survival And Ventricular Enlargement

SOLVD Studies Of Left Ventricular Dysfuntion

Val-HeFT Valsartan in Heart Failure Trial

VALIANT VALsartan In Acute myocardial INfarcTion

234

surveys show similar results, ie, aworrying underuse of ACE inhibitorsand even more of β-blockers in CHFpatients. Surveys conducted in thecommunity, in hospital patients, orin ambulatory patients at the timeof the publication of the updatedversion of the ESC guidelines, revealan overall rate of prescription ofACE inhibitors in the range of 60%and less than 15% for β-blockers(Figure 1).12-14 The Euro Heart Fail-ure Survey (2001-2002), which en-

rolled more than 11 000 in-hospitalpatients across 24 ESC countriesindicates that, overall, only 63% and37% of patients were on ACE inhib-itors and β-blockers, respectively,at discharge, and that daily dosageof β-blockers was markedly belowthe target dose used in random-ized trials.15 Even in the subgroupof patients with depressed systolicfunction did the rate of prescriptionof β-blockers remain below 50%.These consistent observations sug-gest that dual neuhormonal inhibi-tion, although strongly recommend-ed, remains poorly implemented inreal life both in terms of rate of pre-scription and daily dosage.

The reasons for this gap betweencurrent practice and guidelines aremany and include educational is-sues; reluctance to use “new con-

cept” drugs; contraindications orside effects; and difficulty to adhereto the time-consuming stepwiseuptitration required for β-blockers.Whatever the reason, the upshot isthat, in practice, fewer than 50% ofpatients who ought to be on bothACE inhibitors and β-blockers actu-ally receive them. Of note, the EuroHeart Failure Survey suggests thatelderly patients (>70 years) are lesslikely to receive the dual neurohor-monal therapy.

ALTERNATIVES TO DUAL NEUROHORMONALTHERAPY AND MULTIPLE

NEUROHORMONAL THERAPY

Angiotensin II type 1 receptor antagonists (ARBs)

The development of new modula-tors of the renin-angiotensin system(RAS)—the angiotensin II type 1receptor blockers (ARBs, aka sar-tans)—has raised new hopes for thetreatment of heart failure. In theo-ry, a potential advantage of sartansover ACE inhibitors would be toblock the effect of “alternative” an-giotensin II generation pathwaysthat bypass ACE inhibition, such asthe chymase pathway, by blockingthe angiotensin II type 1 (AT1) re-ceptor.

Below is a brief discussion of thefindings from large randomized, con-trolled outcome studies performedover the past 5 years in the wake ofseveral pilot studies.

• ARB-mediated neuromodulationusing losartan 50 mg/day was notfound to be superior to ACE inhibi-tion in terms of mortality and vari-ous outcome measures in CHF andpost–myocardial infarction (Evalua-tion of Losartan In The Elderly II[ELITE II]16; OPtimal Trial In Myocar-dial infarction with Angiotensin IIAntagonist Losartan [OPTIMAAL]17).• In myocardial infarction with heartfailure, left ventricular dysfunction,or both, the effect of valsartan onmortality was not inferior to that ofcaptopril (VALsartan In Acute myo-cardial INfarcTion [VALIANT]18).• In patients not receiving an ACEinhibitor due to intolerance, themagnitude of the beneficial effecton morbidity and mortality is simi-lar to the effect observed with ACEinhibitors (Candesartan in Heartfailure Assessment of Reduction inMortality [CHARM-alternative]19). • In combination with ACE inhibi-tors, ARBs significantly reduce heartfailure hospitalizations (Valsartan–Heart Failure Trial [Val-HeFT]20;CHARM-added21) or cardiovasculardeath (CHARM-added). The benefi-cial effect of comprehensive RASinhibition by the combination ofACE inhibitors and ARBs seemsparticularly important in patientsnot receiving a β-blocker.22

• The potential negative interactionof triple inhibition using ACE inhib-itors, ARBs, and β-blockers, whichwas discussed in the first trials(ELITE II, Val-HeFT) was not con-firmed subsequently and might havebeen a chance occurrence.• A dose effect is discussed, as dos-es used in “positive” trials such asCHARM, VALIANT were high, where-as in ELITE II or OPTIMAAL—whichfailed to demonstrate superiority



Community In hospital AmbulatoryZannad et al,12 1999 Cohen-Solal et al,13 2000 Komajda et al,14 2001

74.8%

5.3%

56%

7%

54%

14%

ACE inhibitor

β-Blocker

Figure 1. Rate of prescription of angiotensin-converting enzyme (ACE) inhibitors and �-blockers in three national surveys.

or noninferiority compared with ACEinhibitors—the doses of losartanused were rather low (approximate-ly 50 mg/day).

Aldosterone antagonists

The Randomized ALdactone Evalua-tion Study (RALES) was performedin patients with severe CHF, NYHAClass III or IV, and a history of classIV in the 6 months prior to random-ization, with a severely depressedejection fraction below 30%.23 Itcompared the addition of spirono-lactone 25 to 50 mg/day on top ofdiuretics, ACE inhibitors, and inmost instances, digitalis to thisbackground therapy. The study wasprematurely terminated due to themagnitude of the benefit observedin the spironolactone arm on mor-tality (-30%) and on hospitalizations,particularly heart failure hospital-izations (-35%). More recently, theselective aldosterone blocker eple-renone, 25 to 50 mg/day, was evalu-ated in acute myocardial infarctioncomplicated by left ventricular dys-function and heart failure, showinga significant 15% risk reduction inall-cause mortality and a 13% re-duction in cardiovascular death orhospitalizations.24

These two trials therefore suggestthat aldosterone blockade is anoth-er successful approach to improvingoutcome both in chronic heart fail-ure and in high-risk myocardial infarction. In this context, it is rele-vant to examine the backgroundtherapy used in these two trials withregard to β-blockers: in RALES,only 11% of the patients were on β-blockers, in contrast to 75% of thepatients enrolled in the EplerenonePost-AMI Heart failure Efficacy andSUrvival Study (EPHESUS). Thissuggests that, for historical reasons,the benefit observed with spirono-lactone did not fall within the con-text of recommended “modern”

neurohormonal modulation, as op-posed to eplerenone, for which thebenefit was demonstrated in thecontext of current treatment guide-lines for myocardial infarction.

MULTIPLE NEUROHORMONAL

MODULATION IN PRACTICE

Based on the evidence reviewedabove, the following recommenda-tions can be made:

Neurohormonal blockade appliesonly to patients with depressed sys-tolic function defined by an ejectionfraction below 35% to 40%. The levelof evidence regarding heart failurewith preserved systolic function ispoor, outside of CHARM-preserved,which enrolled patients with anejection fraction of 40% or more, athreshold that already suggests asomewhat altered ejection fraction).Indeed, CHARM-preserved suggest-ed that the ARB candesartan led toa reduction in the number of heartfailure hospitalizations, but the trialfell short of demonstrating im-proved survival, possibly due to in-sufficient power.

Patients with asymptomatic left ven-tricular dysfunction should receivean ACE inhibitor and, in the con-text of post–myocardial infarction, aβ-blocker. Symptomatic CHF patientsshould receive an ACE inhibitor, aβ-blocker unless contraindicated,and a diuretic (Figure 2). If the pa-tient improves, the diuretic shouldbe downtitrated to the lowest dosagecompatible with a good quality oflife in order to avoid potential harm-ful effects of high diuretic dosageon the RAS. Conversely, every effortshould be made to uptitrate bothACE inhibitors and β-blockers tothe maximal tolerated dose close tothe target dose used in clinical tri-als. Although there are few data tosupport this practice, many expertsprefer to give ACE inhibitors and β-blockers at a “medium” dosage inorder to ensure simultaneous goodtolerance of both drugs, rather thangiving the maximal dose of ACE inhibitor, which might limit the in-troduction and uptitration of the β-blocker. The order of prescriptionremains ACE inhibitor first, followedby the β-blocker when the patient isin stable condition, as all β-blockertrials have been designed with a

235235



Improved

Diuretic

➔

Not improved

Add ARB/spironolactone

Add both, DIG, resync., nitrates

Check dosage/compliance; inotropes

ARB (if intolerant to ACE inhibitor or β-blocker)

ACE inhibitor + diuretic + β-blocker

SYMPTOMATIC HEART FAILURE

Figure 2. Algorithm for the combination of neurohormonal modulators in symptomaticpatients with CHF. Resync., resynchronization therapy.



236

background therapy of ACE inhib-itors. However, some data suggestthat the introduction of the β-block-er first is just as well tolerated.25

If the patient is intolerant to ACEinhibition or β-blockers, an ARBshould be introduced early on incombination with an ACE inhibitoror a β-blocker. If the patient remainssymptomatic despite this dual neu-rohormonal inhibition, a third neu-rohormonal modulator should thenbe used. Given the fact that inCHARM-added patients were in aless severe category and were moreoften treated with β-blockers thanin RALES, one might give the pref-erence to ARBs in chronic heart fail-ure. Conversely, more patients inCHARM-added had to be withdrawnfrom the trial for serious adversereactions (24%), including hypoten-sion and increase in creatinine orhyperkalemia, than in RALES (8%).

In post–myocardial infarction withheart failure or left ventricular dys-function, use of an aldosterone an-tagonist such as eplerenone (notyet licensed in many countries) canbe recommended. If the patient remains severely symptomatic de-spite triple neurohormonal therapy,then the use of four neuromodula-tors should be considered (ACE inhibitor+β-blocker+ARB+aldos-terone antagonist). Due to the po-tential risk of hypotension, hyper-kalemia, and renal dysfunction inthis situation, regular monitoring ofblood pressure, serum potassium,and serum creatinine is mandatoryupon initiation and during follow-up.Another option at this stage is toconsider resynchronization therapy.

LIMITATIONS AND FUTUREOPTIONS FOR NEURO-

HORMONAL MODULATION

One of the limitations of long-termneurohormonal modulation is sug-gested by the findings of the 12-year

follow-up of SOLVD patients: theabsolute risk reduction in all-causemortality in the symptomatic pa-tients initially treated with the ACEinhibitor enalapril was only 1%, and4 out of 5 patients had died at theend of follow-up.26 This illustratesthat although active therapy didslow down the mortality rate, in theend, a majority of symptomaticdied at 12 years, particularly due tononcardiac reasons. Conversely, the12-year absolute risk reduction inmortality remained substantial inthe asymptomatic patients (5.5%),suggesting that the earlier the neu-rohormonal modulation, the better.

Other therapeutic options have re-cently been tested in CHF. Interestfocused on endothelin antagonists,but, despite theoretical potentialadvantages, these agents failed todemonstrate any clinical benefit ontop of ACE inhibitors and β-block-ers. Among the various hypothesesraised to explain this failure, one is that a ceiling of neurohormonalblockade is reached with the suc-cessful combination of an ACE in-hibitor and a β-blocker or an ARBand a β-blocker, leaving very littleroom for further improvement withadditional blockade.

Similarly, the dual ACE/neutral en-dopeptidase inhibitor omapatrilatefailed to demonstrate any benefitagainst captopril, thus suggestingthat, so far, this complex type of neu-rohormonal modulation is not bet-ter than simple ACE inhibition.27

Finally, several ongoing studies arecurrently assessing the role of argi-nine-vasopressin antagonists inheart failure with hyponatremia.

To conclude, the story of multipleneurohormonal modulation as a keyplayer in CHF management is notover and exciting future develop-ments can be anticipated.

REFERENCES

1. The CONSENSUS Trial study group.

Effects of enalapril on mortality in severecongestive heart failure: results of the Coop-erative North Scandinavian Enalapril Sur-vival Study (CONSENSUS).

N Engl J Med. 1987;316:1429-1435.

2. The Studies of Left VentricularDysfunction (SOLVD) Investigators.

Effects of enalapril on survival in patientswith reduced left ventricular ejection fractionsand congestive heart failure.

N Engl J Med. 1991;325:293-302.

3. Cohn JN, Johnson G, Ziesche S, et al.

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment ofchronic congestive heart failure.

N Engl J Med. 1991;325:303-310.

4. Pfeffer MA, Braunwald E, Moye LA,et al.

Effects of captopril on mortality in patientswith left ventricular dysfunction after myo-cardial infarction. Results of the Survivaland ventricular Enlargement Trial.

N Engl J Med. 1992;327:669-677.

5. The Studies of Left VentricularDysfunction (SOLVD) Investigators.

Effect of enalapril on mortality and the de-velopment of heart failure in asymptomaticpatients with reduced left ventricular ejec-tion fractions.

N Engl J Med. 1992;327:685-691.

6. Remme WJ, Swedberg K, co-chairmen.

Task force for the diagnosis and treatment ofchronic heart failure of the European Societyof Cardiology. Guidelines for the diagnosisand treatment of chronic heart failure.

Eur Heart J. 2001;22:1527-1560.

7. Packer M, Bristow M, Cohn J, et al.

The effect of carvedilol on morbidity andmortality in patients with chronic heartfailure.

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



237

8. Anon.

The Cardiac Insufficiency Bisoprolol Study II(CIBIS II): a randomised trial.

Lancet. 1999;353:9-13.

9. Anon.

Effect of metoprolol CR/XL in chronic heartfailure: Metoprolol CR/XL Randomised In-tervention trial in Congestive Heart Failure(MERIT-HF).

Lancet. 1999;353:2001-2007.

10. Packer M, Fowler MB, RoeckerEB, et al.

Carvedilol Prospective Randomised Cumula-tive Survival (COPERNICUS) Study Group.Effect of carvedilol on the morbidity of pa-tients with severe chronic heart failure: resultsof the carvedilol prospective randomised cumulative survival study.

Circulation. 2002;106:2194-2199.

11. Dargie HJ.

Effect of carvedilol outcome after myocardialinfarction in patients with left ventriculardysfunction: the CAPRICORN randomisedtrial.

Lancet. 2001;357:1385-1390.

12. Zannad F, Briancon S, Juillière Y,et al, and the EPICAL Investigators.

Incidence, clinical and etiologic features andoutcomes of advanced chronic heart failure.The EPICAL study. Épidémiologie de l’In-suffisance Cardiaque Avancée en Lorraine.

J Am Coll Cardiol. 1999;33:734-742. Er-ratum in J Am Coll Cardiol. 1999;34:1363.

13. Cohen-Solal A, Desnos M, Delahaye F, Emeriau JP, Hanania G.

A national survey of heart failure in FrenchHospitals.

Eur Heart J. 2000;21:763-769.

14. Komajda M, Bouhour JB,Amouyel P, et al.

Ambulatory heart failure management inprivate practice in France.

Eur Heart Fail. 2001;3:503-507.

15. Komajda M, Follath F, SwedbergK, et al.

The Euro Heart Failure Survey programme—a survey on the quality of care among pa-tients with heart failure in Europe.

Eur Heart J. 2003;24:464-475.

16. Pitt B, Poole-Wilson PA, Segal R,et al.

Effect of losartan compared with captoprilon mortality in patients with symptomaticheart failure: randomised trial—the losar-tan heart failure survival study ELITE II.

Lancet. 2000;355:1582-1587.

17. Dickstein K, Kjekshus J, and theOPTIMAAL Steering Committee.

Effects of losartan and captopril on mortalityand morbidity in high-risk patients afteracute myocardial infarction: the OPTIMAALrandomised trial.

Lancet. 2002;360:752-760.

18. Pfeffer MA, McMurray JJV, Velazquez EJ, et al.

Valsartan, captopril or both in myocardialinfarction complicated by heart failure, leftventricular dysfunction or both.

N Engl J Med. 2003 349:1893-1906.

19. Granger CB, McMurray JJV, Yusuf S, et al.

Effects of candesartan in patients with chron-ic heart failure and reduced left ventricularsystolic function intolerant to angiotensinconverting enzyme inhibitors: the CHARM-alternative trial.

Lancet. 2003;362:772-776.

20. Cohn JN, Tognoni G.

A randomised trial of the angiotensin-re-ceptor blocker valsartan in chronic heartfailure.

N Engl J Med. 2001;345:1667-1675.

21. McMurray JJV, Ostergren J,Swedberg K, et al.

Effects of candesartan in patients with chron-ic heart failure and reduced left ventricularsystolic function taking angiotensin con-verting enzyme inhibitors: the CHARM-added trial.

Lancet. 2003;362:767-771.

22. Dimopoulos K, Salukhe T, CoatsA, Mayet J, Piepoli M, Francis D.

Meta-analyses of mortality and morbidityeffects of an angiotensin receptor blocker inpatients with chronic heart failure alreadyreceiving an ACE inhibitor (alone or with abeta blocker).

Int J Cardiol. 2004;93:105-111.

23. Pitt B, Zannad F, Remme WJ, et al.

The effect of spironolactone on morbidityand mortality in patients with severe heartfailure.

N Engl J Med. 1999;341:709-717.

24. Pitt B, Remme WJ, Zannad, et al.

Eplerenone, a selective aldosterone blockerin patients with left ventricular dysfunctionafter myocardial infarction.

N Engl J Med. 2003;348:1309-1321.

25. Komajda M, Lutiger B, Madeira H,et al.

Tolerability of carvedilol and ACE inhibitionin mild heart failure. Results of CARMEN(Carvedilol ACE-Inhibitor Remodelling MildCHF Evaluation).

Eur J Heart Fail. 2004;6:467-475.

26. Jong P, Yusuf S, Rousseau MF,Ahn SA, Bangdiwala SI.

Effect of enalapril on 12-year survival andlife expectancy in patients with left ventricularsystolic dysfunction: a follow up study.

Lancet. 2003;361:1843-1848.

27. Packer M, Califf RM, Konstam MA,et al.

Comparison of omapatrilat and enalapril in patients with chronic heart failure. TheOmapatrilat Versus Enalapril RandomisedTrial of Utility in Reducing Events (OVER-TURE).

Circulation. 2002;106:r21-r27.

238

he introduction of angioten-sin-converting enzyme (ACE)inhibitors, aldosterone block-ers, and β-blockers in the

treatment of chronic heart failure(HF) represents one of the greatsuccess stories of modern medicine.The neurohormonal hypothesisprovided the scientific rationale forthese therapies. According to thisconcept, persistent activation ofneurohormonal systems, such asthe renin-angiotensin-aldosterone(RAAS) system, the sympatheticnervous system, or the endothelinsystem, exerts a deleterious effect

on the heart that is independent ofthe hemodynamic actions of theseendogenous mechanisms. Thera-peutic interventions that block theeffects of these neurohormonal sys-tems are therefore predicted to fa-vorably alter the natural history ofHF.1 More recently, it has becomeapparent that, in addition to neuro-hormones, cytokines are also over-expressed in HF. According to thecytokine hypothesis, cytokines, muchlike the neurohormones, representanother class of biologically activemolecules that are responsible forthe progression of HF.2 Several lines

Why are we unable to completely control the activation of neurohormonal systems in chronicheart failure—and should we?Helmut Drexler, MD; Kai C. Wollert, MD

Department of Cardiology and Angiology - Hannover Medical School - Hannover - GERMANY

The neurohumoral hypothesis pro-vided the rationale for treatingheart failure with angiotensin-con-verting enzyme (ACE) inhibitors, al-dosterone blockers, and �-blockers.Backed by the cytokine hypothesis,the case for incremental benefit fromneurohumoral and cytokine block-ade appeared made. However, thependulum may have swung too far.Clinical trials are releasing evidenceof hypotension, renal insufficiency,and critical loss of adrenergic sup-port. ACE inhibitors and �-blockersare already so successful that addedtreatments do not automaticallyconfer added benefits. More is notnecessarily better. Neurohormonalactivation is, at least in part, ahealthy response to the low cardiacoutput that defines heart failure.Although its partial blockade re-mains an effective treatment, we areonly just beginning to understandwhy at the receptor, postreceptor,and cardiovascular cell type level.

Keywords: neurohormonal activation; chronicheart failure; ACE inhibitor; aldosterone blocker;β-blocker; cytokineAddress for correspondence:Prof Dr Helmut Drexler, Abteilung für Kardiologieund Angiologie, Medizinische Hochschule Han-nover, Carl-Neuberg Straße 1, 30625 Hannover,Germany (e-mail: [email protected])


T


ATLAS Assessment of Treatment with Lisinopril And Survival

BEST Beta-blocker Evaluation of Survival Trial

CHARM Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity

EARTH EndothelinA Receptor antagonist Trial in Heart failure

EPHESUS Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study

HF heart failure

NEP neutral endopeptidase

OVERTURE Omapatrilat Versus Enalapril Randomized Trial ofUtility in Reversing Events

RAAS renin-angiotensin-aldosterone system

RALES Randomized ALdactone Evaluation Study

TNF-α tumor necrosis factor–α

Val-HeFT Valsartan in Heart Failure Trial

VALIANT VALsartan In Acute myocardial iNfarction Trial


239

of evidence indicate that neurohor-monal and cytokine activation isdetrimental in HF. Angiotensin II,norepinephrine, endothelin, andtumor necrosis factor (TNF)-α aredirectly cytotoxic to cardiomyocytesand promote adverse myocardialand remodeling in experimentalmodels.3 In patients with HF, activa-tion of these systems is proportionalto disease severity, increases withthe progression of the disease, andis related to prognosis.4 Moreover,changes in neurohormonal activa-tion over time occurring either spon-taneously or in response to phar-macologic therapy are associatedwith proportional changes in subse-quent morbidity and mortality.5 Thesuccess accrued from inhibiting theRAAS and sympathetic nervoussystem has led to the propositionthat a concerted approach to inhibitevery single neurohormonal andcytokine system may provide incre-mental benefits. However, recentclinical trial data evaluating this all-encompassing strategy have yieldedstart-lingly disappointing resultsand indicate that there may be limitsto the classic neurohormonal andcytokine models, and that too muchneurohormonal blockade may evenbe harmful.4,6

MORE COMPLETE ACE INHIBITION

The first hints that we may havereached a therapeutic ceiling in ourefforts to achieve more and morecomplete neurohormonal blockadehave emerged from clinical studiescomparing high-dose versus low-dose ACE inhibition in HF patients.In the Assessment of Treatment withLisinopril And Survival (ATLAS) tri-al, patients with symptomatic HFand a left ventricular ejection frac-tion below 30% were randomly as-signed to a high (target dose 35 mgdaily) or low dose (5 mg) of lisino-pril.7 Patients in the high-dose

group experienced 24% fewer hos-pitalizations for HF. However, high-dose ACE inhibition was associatedonly with a nonsignificant 8% lowermortality rate, the primary end pointof the ATLAS trial. At the same time,renal insufficiency and dizzinesswere observed more frequently inthe high-dose group, confirming thatACE plays a supportive role in main-taining kidney function and bloodpressure in HF.7 A study comparinga very high dose of enalapril (60 mg)with a standard dose (20 mg) inpatients with advanced HF did notfind significant differences in survivaland clinical end points between thetwo groups.8 However, tolerabilityof the high-dose regimen was limit-ed, as evidenced by an excessivewithdrawal rate.8 The lack of benefitof high-dose ACE inhibition maybe related to the phenomenon ofangiotensin II and aldosterone es-cape.9,10 Indeed, high-dose enalapril(40 mg) does not provide greatersuppression of circulating angioten-sin II and aldosterone levels in HFpatients compared with low-doseenalapril (5 mg).10

MORE COMPLETE RAAS INHIBITION

According to the neurohormonalhypothesis, addition of angiotensinreceptor blockers or aldosteroneblockers to a stable regimen of ACEinhibitors and β-blockers would beexpected to provide additional ther-apeutic benefit by counteracting theangiotensin II and aldosterone es-cape, thereby providing more com-plete neurohormonal coverage.11

Indeed, two large clinical trials con-ducted either in patients with severeHF (Randomized ALdactone Evalu-ation Study, RALES) or in patientswith acute myocardial infarction, re-duced left ventricular ejection frac-tion, and HF symptoms (EplerenonePost-acute myocardial infarctionHeart failure Efficacy and SUrvival

Study, EPHESUS) have demonstrat-ed that treatment with aldosteroneblockers results in a further reduc-tion in all-cause mortality (-30% inRALES, -15% in EPHESUS).12-14

Nonjudicious use of aldosteroneblockers in HF, however, may leadto life-threatening episodes of hy-perkalemia, indicating that aldo-sterone plays an important role inmaintaining potassium homeosta-sis, especially in HF patients alreadyreceiving an ACE inhibitor (manyof whom display some degree ofrenal insufficiency), and that closemonitoring of serum potassiumlevels is mandatory when using al-dosterone blockers in HF.15 Com-bination of ACE inhibitors and an-giotensin receptor blockers has beencheered as a means to overcomethe angiotensin II escape observedwith ACE inhibitors alone, and toachieve incremental benefits inHF.11 However, studies investigat-ing whether angiotensin receptorblockers on top of ACE inhibitorsand β-blockers provide additionalbenefit have provided quite disap-pointing results. In the Valsartan inHeart Failure Trial (Val-HeFT), ad-dition of valsartan did not affectoverall mortality (relative risk 1.02)and had only a modest effect on acomposite mortality and morbidityend point (relative risk 0.87) in HFpatients already being treated withACE inhibitors (93%) and β-block-ers (35%).16 Subgroup analyses re-vealed that this benefit was great-est in patients not taking an ACEinhibitor and was no longer statis-tically significant among those whowere on ACE inhibitor and angio-tensin receptor blocker combinationtherapy.16,17 Although valsartan wasgenerally well tolerated, hypotensionand renal impairment were notedmore frequently in the valsartangroup.16 Not surprisingly so, be-cause the AT1 receptor is critical forblood pressure control and kidneyfunction, also in HF!


Why are we unable to control the activation of neurohormonal systems in CHF? - Drexler and Wollert

240

In the Candesartan in Heart failureAssessment of Reduction in Mor-tality and morbidity (CHARM)-addedtrial, treatment with candesartan inpatients receiving ACE inhibitors(100%) and β-blockers (55%) exerteda modest beneficial effect on theprimary end point of combined car-diovascular death or hospital ad-mission with HF (hazard ratio 0.85),but did not significantly reduceall-cause mortality (hazard ratio0.89).18 Increases in creatinine andhyperkalemia were observed morefrequently in candesartan-treatedpatients.18 In the VALsartan InAcute myocardial iNfarction Trial(VALIANT), patients with myocardialinfarction complicated by left ven-tricular systolic dysfunction and/orHF were randomly assigned to cap-topril, valsartan, or captopril andvalsartan.19 Although valsartan wasnot inferior to captopril in reducingall-cause mortality, combinationtherapy with valsartan and captoprildid not provide any additional ben-efits on mortality and morbiditybeyond monotherapy with eitheragent.19 Similar to Val-HeFT, hypo-tension and renal insufficiency wereobserved more frequently in patientsreceiving combination therapy.19

MORE COMPLETE SYMPATHETIC NERVOUS

SYSTEM INHIBITION

Little information is available re-garding the dose dependency of theeffects of β-blockers in HF. In onestudy, patients with mild to moder-ate HF were randomized to receivelow-dose (6.25 mg bid), medium-dose (12.5 mg bid), or high-dose(25 mg bid) carvedilol treatment (the“high dose” actually represents therecommended target dose for carve-dilol in HF patients). In this study,carvedilol produced dose-related im-provements in left ventricular func-tion and dose-related reductions inmortality and hospitalization rate.20

Additional clues may be derived bylooking at some early β-blocker trialsthat have used relatively low dosesof β-blockers and did not demon-strate as impressive benefits as latertrials using the now recommendeddoses of the same agents.17,21 Sur-prisingly, in the Beta-blocker Evalua-tion of Survival Trial (BEST), class IVpatients receiving bucindolol whohad a marked decrease in circulat-ing norepinephrine levels from base-line experienced an increase in mor-tality, as compared with patientswho had no significant change innorepinephrine levels.22,23 More-over, the observation that moxoni-dine, a centrally-acting sympa-tholytic agent, decreases plasmanorepinephrine levels, but adverselyaffects survival in HF patients, hasraised concerns regarding the effi-cacy of a generalized sympatheticinhibition in HF.24 This may sug-gest, that excessive inhibition of thesympathetic nervous system resultsin a critical loss of adrenergic sup-port and adverse outcomes in HFpatients.

INHIBITION OF ADDITIONAL NEURO-

HORMONAL/CYTOKINESYSTEMS

It has recently been attempted toexpand the benefits derived fromACE inhibitors by combining ACEinhibition with inhibition of otherpeptidases such as neutral endopep-tidase (NEP) in a single molecule,a strategy known as vasopeptidaseinhibition. NEP metabolizes natriu-retic peptides, and NEP inhibitionoffers the prospect of combining thebenefits of increased vasodilatorynatriuretic peptide levels with thoseof ACE inhibition. However, NEPalso converts angiotensin I to thevasodilatory angiotensin (1-7) pep-tide and metabolizes angiotensin IIand endothelin. Addition of NEPinhibition to ACE inhibition there-

fore reduces angiotensin (1-7) levels,and may increase angiotensin IIand endothelin levels. These addi-tional consequences of combinedACE/NEP inhibition may counteractany benefit of ACE inhibition.25

In the OVERTURE trial (OmapatrilatVersus Enalapril Randomized Trialof Utility in Reducing Events) thevasopeptidase inhibitor omapatrilatwas found not to be superior toenalapril with regard to the primarycombined end point of risk of deathor hospitalization for HF requiringintravenous treatment.26 Hypoten-sion and dizziness were reportedmore frequently with omapatrilat,especially in patients with low pre-treatment systolic blood pressure.26

This is another example that theoccurrence of hypotension maylimit our efforts at more aggressiveneurohormonal blockade.

Endothelin has been suggested tocontribute to the pathophysiologyof HF very much like angiotensin IIand norepinephrine. However, sev-eral studies have failed to demon-strate that endothelin antagonistsprovide clinical benefit. The mixedETA and ETB receptor blocker bosen-tan promoted early worsening ofHF, but later symptomatic improve-ment, when given at a high dose;low-dose bosentan, however, did notimprove clinical outcome (reviewedin reference 4). Because selectiveETB receptor blockade may worsenhemodynamics in HF patients,27 itwas suggested that selective ETA

receptor blockade may be more effective than mixed ETA and ETB

blockade. However, in the recentlycompleted EndothelinA Receptorantagonist Trial in Heart failure(EARTH), the ETA receptor blockerdarusentan did not add incrementalbenefit in patients already receiv-ing an ACE inhibitor (98%) and aβ-blocker (80%).4,28 Studies in ex-perimental models and preliminary



241



clinical experience suggested a pos-sible therapeutic role for the solu-ble TNF-α antagonist etanercept inHF. However, etanercept had no ef-fect on clinical status and a com-bined death or HF hospitalizationend point in two recently completedclinical trials.29 Although one inter-pretation of these disappointingresults is that TNF-α is not a viabletarget in HF in patients already re-ceiving ACE inhibitors and β-block-ers, a countervailing point of viewis that we have not targeted TNF-αwith the right agent, or alternatively,that targeting a single componentof the inflammatory cascade is notsufficient in a disease as complexas HF. Moreover, these trials do notexclude the possibility that thereexists a select group of patients inwhom TNF-α antagonism may bebeneficial.29

WHY MORE IS NOT NECESSARILY BETTER

Why did our recent attempts atmore complete neurohormonal andcytokine blockade fail to significant-ly impact on the prognosis of HF?First of all, it should be noted thatrecent strategies were tested in pa-tients many of whom were alreadyreceiving effective ACE inhibitorand β-blocker therapy. Any potentialsurvival benefit of a new agent there-fore had to be demonstrated on topof these extremely successful treat-ments. We will never know whethernewer therapies are in fact, as goodas, or even better than ACE inhib-itors or β-blockers alone.

Secondly, ACE inhibitors and β-blockers are already extremelyefficacious in reducing morbidityand mortality in HF. Consider, forexample, the subgroup of patientsin the Val-HeFT trial receiving bothan ACE inhibitor and a β-blocker:this subgroup experienced an annu-al mortality rate of only 5.7%. Thus,

at least in the setting of clinical tri-als, effective use of ACE inhibitorsand β-blockers has already reducedthe mortality rate of patients withmoderate to severe HF to a remark-ably low level, considering that, according to the National Vital Sta-tistics Report, the annual mortalityrate in white American men aged65 years without HF is approximate-ly 3%.4 It is possible that angiotensinreceptor blockers, vasopeptidaseinhibitors, or endothelin antagonistswould provide greater therapeuticbenefit if they were used as first-linetreatments in HF patients (as theydid in experimental models).30-32

Thirdly, we may have to revise ourthinking that neurohormonal acti-vation is entirely harmful in the set-ting of HF. Despite the recent re-finements in our understanding ofthe cellular, molecular, genetic, andinflammatory alterations in HF, lowcardiac output remains the patho-physiological basis of the disease.Neurohormonal activation repre-sents an ancient defense system tomaintain blood pressure, blood vol-ume, water and electrolyte homeo-stasis, and renal function duringacute or chronic volume loss (eg,after trauma or starvation). It is thereduction of cardiac output in HFthat leads to neurohormonal activa-tion. Not surprisingly, hypotension,renal dysfunction, and hyperkalemiaare encountered in many patientswhere maximum neurohormonalblockade is attempted, and thebody’s own homeostatic mecha-nisms are undermined.

Finally, let’s be honest, we do notreally understand why neurohor-monal blockade is so effective in HF.We are only beginning to appreciatewhat neurohormonal antagonistsdo at the receptor and postreceptorlevel, and what the consequences atthe (post)transcriptional level are indistinct cardiovascular cell types.33

REFERENCES

1. Packer M.

The neurohormonal hypothesis: a theory toexplain the mechanism of disease progres-sion in heart failure.


2. Seta Y, Shan K, Bozkurt B, Oral H,Mann DL.

Basic mechanisms in heart failure: the cyto-kine hypothesis.

J Card Fail. 1996;2:243-249.

3. Braunwald E, Bristow MR.

Congestive heart failure: fifty years ofprogress.

Circulation. 2000;102:IV14-IV23.

4. Anand IS.

Is too much neurohormonal blockadeharmful?

Curr Cardiol Rep. 2004;6:169-175.

5. Anand IS, Fisher LD, Chiang YT, et al.

Changes in brain natriuretic peptide andnorepinephrine over time and mortality andmorbidity in the Valsartan Heart FailureTrial (Val-HeFT).

Circulation. 2003;107:1278-1283.

6. Mehra MR, Uber PA, Francis GS.

Heart failure therapy at a crossroad: arethere limits to the neurohormonal model?

J Am Coll Cardiol. 2003;41:1606-1610.

7. Packer M, Poole-Wilson PA, Armstrong PW, et al.

Comparative effects of low and high doses ofthe angiotensin-converting enzyme inhibitor,lisinopril, on morbidity and mortality inchronic heart failure. ATLAS Study Group.

Circulation. 1999;100:2312-2318.

8. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al.

Outcome of patients with congestive heartfailure treated with standard versus highdoses of enalapril: a multicenter study.High Enalapril Dose Study Group.

J Am Coll Cardiol. 2000;36:2090-2095.

242



9. Jorde UP, Ennezat PV, Lisker J, et al.

Maximally recommended doses of angioten-sin-converting enzyme (ACE) inhibitors donot completely prevent ACE-mediated forma-tion of angiotensin II in chronic heart failure.

Circulation. 2000;101:844-846.

10. Tang WH, Vagelos RH, Yee YG,et al.

Neurohormonal and clinical responses tohigh- versus low-dose enalapril therapy inchronic heart failure.


11. Azizi M, Menard J.

Combined blockade of the renin-angiotensinsystem with angiotensin-converting enzymeinhibitors and angiotensin II type 1 receptorantagonists.

Circulation. 2004;109:2492-2499.

12. Pitt B, Zannad F, Remme WJ, et al.

The effect of spironolactone on morbidityand mortality in patients with severe heartfailure. Randomized Aldactone EvaluationStudy Investigators.

N Engl J Med. 1999;341:709-717.

13. Pitt B.

Aldosterone blockade in patients with sys-tolic left ventricular dysfunction.

Circulation. 2003;108:1790-1794.

14. Pitt B, Remme W, Zannad F, et al.

Eplerenone, a selective aldosterone blocker,in patients with left ventricular dysfunctionafter myocardial infarction.

N Engl J Med. 2003;348:1309-1321.

15. Bozkurt B, Agoston I, Knowlton AA.

Complications of inappropriate use ofspironolactone in heart failure: when anold medicine spirals out of new guidelines.


16. Cohn JN, Tognoni G.

A randomized trial of the angiotensin-receptorblocker valsartan in chronic heart failure.

N Engl J Med. 2001;345:1667-1675.

17. Massie BM.

Neurohormonal blockade in chronic heartfailure. How much is enough? Can there betoo much?


18. McMurray JJ, Ostergren J, Swedberg K, et al.

Effects of candesartan in patients with chron-ic heart failure and reduced left-ventricularsystolic function taking angiotensin-convert-ing-enzyme inhibitors: the CHARM-Addedtrial.

Lancet. 2003;362:767-771.

19. Pfeffer MA, McMurray JJ, Velazquez EJ, et al.

Valsartan, captopril, or both in myocardialinfarction complicated by heart failure, leftventricular dysfunction, or both.

N Engl J Med. 2003;349:1893-1906.

20. Bristow MR, Gilbert EM, AbrahamWT, et al.

Carvedilol produces dose-related improve-ments in left ventricular function and sur-vival in subjects with chronic heart failure.MOCHA Investigators.

Circulation. 1996;94:2807-2816.

21. Wollert KC, Drexler H.

Carvedilol prospective randomized cumulativesurvival (COPERNICUS) trial: carvedilol asthe sun and center of the beta-blocker world?

Circulation. 2002;106:2164-2166.

22. Beta-Blocker Evaluation of Survival Trial Investigators.

A trial of the beta-blocker bucindolol in pa-tients with advanced chronic heart failure.

N Engl J Med. 2001;344:1659-1667.

23. Bristow MR, Krause-Steinrauf H,Abraham WT, et al.

Sympatholytic effect of bucindolol adverselyaffected survival, and was disproportionatelyobserved in the class IV subgroup of BEST.

Circulation. 2001;104:II755.

24. Cohn JN, Pfeffer MA, Rouleau J,et al.

Adverse mortality effect of central sympatheticinhibition with sustained-release moxonidinein patients with heart failure (MOXCON).

Eur J Heart Fail. 2003;5:659-667.

25. Campbell DJ.

Vasopeptidase inhibition: a double-edgedsword?

Hypertension. 2003;41:383-389.

26. Packer M, Califf RM, Konstam MA,et al.

Comparison of omapatrilat and enalapril inpatients with chronic heart failure: the Oma-patrilat Versus Enalapril Randomized Trialof Utility in Reducing Events (OVERTURE).

Circulation. 2002;106:920-926.

27. Wada A, Tsutamoto T, Fukai D,et al.

Comparison of the effects of selective endo-thelin ETA and ETB receptor antagonists incongestive heart failure.

J Am Coll Cardiol. 1997;30:1385-1392.

28. Anand I, McMurray J, Cohn JN, etal.

Long-term effects of darusentan on left-ven-tricular remodelling and clinical outcomes inthe EndothelinA Receptor Antagonist Trialin Heart Failure (EARTH): randomised,double-blind, placebo-controlled trial.

Lancet. 2004;364:347-354.

29. Mann DL, McMurray JJ, Packer M,et al.

Targeted anticytokine therapy in patients withchronic heart failure: results of the Ran-domized Etanercept Worldwide Evaluation(RENEWAL).

Circulation. 2004;109:1594-1602.

30. Sakai S, Miyauchi T, Kobayashi M,Yamaguchi I, Goto K, Sugishita Y.

Inhibition of myocardial endothelin pathwayimproves long-term survival in heart failure.

Nature. 1996;384:353-355.

31. Kim S, Yoshiyama M, Izumi Y, et al.

Effects of combination of ACE inhibitor andangiotensin receptor blocker on cardiac remodeling, cardiac function, and survivalin rat heart failure.

Circulation. 2001;103:148-154.

32. Cataliotti A, Boerrigter G, ChenHH, et al.

Differential actions of vasopeptidase inhibi-tion versus angiotensin-converting enzymeinhibition on diuretic therapy in experimentalcongestive heart failure.

Circulation. 2002;105:639-644.

33. Rockman HA, Koch WJ,Lefkowitz RJ.

Seven-transmembrane-spanning receptorsand heart function.

Nature. 2002;415:206-212.


243

he classification of antiarrhyth-mic drugs proposed by Singhand Vaughan Williams in 19701,2

relied on the differential actionsof these agents on the profile of thetransmembrane action potential inisolated myocardial tissue from differ-ent species. Despite the dramatic ad-vances over the last 15 years in under-standing the molecular and ionic basis,which determine the profile of thetransmembrane action potential, theoriginal classification persists in boththe clinical and government regulatoryspheres. The field of Class III antiar-rhythmic drug research has been illu-minated by numerous publications ina most fruitful manner over the last30 years by Professor Bramah Singh,who provides an elegant example ofwhat is now translational medicine,ie, applying data from the laboratoryto the bedside. This essay is largelybased on Professor Singh’s seminalwork.3-7

FIRST-GENERATION CLASS III AGENTS:AMIODARONE AND

SOTALOL

Amiodarone and sotalol provide strik-ing examples of the role of serendipityin drug discovery. Amiodarone was ini-tially developed as a selective coronary

vasodilator for the treatment of angi-na pectoris, and sotalol was a nonse-lective β-blocker first synthesized atthe same time as the classic β-blockerspronethalol and propranolol (1959-1962).

DISCOVERY OFAMIODARONE

Amiodarone was one of a large numberof benzofuran analogs synthesized inthe Labaz Laboratories in Belgium be-tween 1958-1966.8,9 The rationale forthe synthetic program was based onthe natural product, khellin, which wasused in the Middle East as a diureticand antispasmodic. Khellin was isolat-ed from the seeds of the plant Ammivisnaga, called in Arabic “khella.” Thefirst paper from the Labaz Laboratoriesdescribes the coronary vasodilatorproperties of a series of benzofuransderived from the furanochromonestructure of khellin.9 In regard to therationale for the research program, thepaper quotes the work of Anrep et al10

published in 1945, which concludedthat khellin (120 mg daily) was effectivein 36 of 38 anginal patients. The Labazpaper also notes that Greiner et al11

had failed to confirm Anrep’s observa-tions. Nevertheless, the Labaz scien-tists appear to have concluded that theproof of concept of the antianginalaction of khellin was established. Fur-thermore, the khellin preparation wasmarketed by Smith-Kline in the early1950s and is still classified in the Mar-tindale Extra Pharmacoepia underSupplementary Drugs and Other Sub-stances.12

Eighty-one benzofurane analogs weresynthesized and tested in vitro fortheir antispasmodic activity on smoothmuscle as well as their coronary dilat-ing action in the isolated, fibrillating,rabbit heart. In these in vitro tests,khellin was used as the benchmarkcoronary vasodilator.9 CompoundL2329 (Amplivix®, benziodarone) wasdeveloped for clinical studies in anginapectoris.13,14

Clinical trials in the early 1960s showedthat it was effective in reducing thenumber of anginal attacks and increas-ing exercise tolerance. It was also ob-served that it slowed the heart rate. Apaper from the Labaz Laboratories in196915 states that a clinical investiga-tor had observed that amiodarone hadantiarrhythmic properties. The pub-lished paper14 does not refer to a re-duction of arrhythmias, but only ofheart rate in anginal patients treatedwith amiodarone 600 mg daily for amonth. Interestingly, the paper reportsthat “the depolarization complex ofthe ECG showed no change.” The in-troduction to the paper by Charlier etal15 refers to “a chance observation of normalization of cardiac rhythm inan anesthetized dog following amio-darone 10 mg/kg/ IV,” although thepaper they quote contains only clinicalstudies in anginal patients.

Nevertheless, the Labaz scientists re-evaluated amiodarone in several ex-perimental arrhythmia models and attributed their positive findings to acombination of the sympatholytic andquinidine-like actions of amiodarone.15

Address for correspondence:Dr J. Desmond Fitzgerald, Materia Medica, MereCroft, Chester Road, Mere, Knutsford, CheshireWA16 6LG, UK(e-mail: [email protected])


T

Trails of Discovery Class III antiarrhythmic agents: serendipity or drug design?

J. Desmond Fitzgerald, BSc, FRCP, FFPMMateria Medica - Mere, Knutsford - UK

During this same period, VaughanWilliams’ group in Oxford published aseries of papers examining the effectsof different drugs on the myocardialtransmembrane action potential. Thesestudies resulted in a proposal to clas-sify antiarrhythmic drugs into at leastthree categories.2 His group had alsoobserved the effects of experimentalhypothyroidism on the transmem-brane action potential in rabbits andshowed that six weeks after thyroidec-tomy the action potential duration wassignificantly prolonged (Figure 1a).16

Dr Bramah Singh, who was a Common-wealth Fellow born in Fiji and trainedin medicine in Otago University, New

Zealand, joined Professor VaughanWilliams group in the late 1960s inorder to do a PhD degree. The topicchosen was “The study of the pharma-cological actions of certain drugs andhormones with a particular referenceto cardiac muscle.” Included in thisresearch program was an evaluationof the effects of chronic amiodaronetreatment on the transmembrane ac-tion potential after chronic administra-tion (20 mg/kg IP) to rabbits. He showedthat amiodarone specifically prolongedthe action potential duration (APD)without significant effects on the rest-ing potential or the rate of rise of theaction potential (Figure 1b). The pre-cise rationale for selecting amiodarone

for study is not stated in the publishedpapers or the thesis. One may specu-late that it was the di-iodo substitutionin amiodarone that was the stimulusfor its selection, though it was claimedat the time to have no effect on thy-roid function. In addition, amiodaronehad complex effects on the autonomicsystem, causing an atropine-resistantbradycardia in dogs and inhibition ofsympathetic nerve stimulation andcatecholamines, but not due to specif-ic blockade of α or β adrenoceptors.17

This combination of pharmacologicalattributes made it an interesting toolfor exploring the mode of action ofantiarrhythmic compounds.


Class III antiarrhythmic agents: serendipity or drug design? - Fitzgerald

244

50 mV

THYROIDECTOMY

HYPERTHYROID

CONTROL

100 ms slow

50 mV100 V/s

50 mV

5 ms fast

100 ms slow5 ms fast

100 mV

0

CONTROL

AMIODARONE

CONTROL

AMIODARONE

100 ms slow

100 mV

0

50 mV

300 V/s

dV/dt0

100 V/s

50 mV

5 ms fast

200 ms slow6 ms fast

Figure 1a. The effect of thyroid state on cardiac intracellular potentials.The horizontal line in each frame indicates the zero potential and thesuperimposed traces record intracellular action potentials at both slow andfast sweep speeds. The lowest trace records the contractile response.

From reference 16: Freedberg AS, Papp J, Vaughan Williams EM. Theeffect of altered thyroid state on atrial intracellular potentials. J PhysiolLond. 1970;207:357-370. Copyright © 1970, Blackwell Publishing.

Figure 1b. The effects of 6 weeks treatment with amiodarone (20 mg/kg/IPdaily) in rabbit atrial muscle, above, and in ventricular muscle, below.

From reference 3: Singh BN, Vaughan Williams EM. The effects ofamiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol.1970;39:657-667. Copyright © 1970, Nature Publishing Group.

245

CLINICAL STUDIES

The major clinical utility of amiodaroneis in the prophylactic control of supra-ventricular and ventricular arrhyth-mias. Parenteral amiodarone (5 mg/kgby slow injection) slows the ventricularresponse in atrial flutter and fibrilla-tion. Observational studies suggestthat it is also effective acutely in thecontrol of life-threatening ventriculararrhythmias.18 It’s major utility is aschronic therapy (200-400 mg daily),firstly to control the ventricular re-sponse in atrial flutter and fibrillationboth at rest and on exercise. Secondly,amiodarone has had a major impacton the treatment of recurrent life-threatening ventricular tachyarrhyth-mias. It is currently the drug of choicefor this indication. Remarkably, it hasmuch less proarrhythmic activity thanmany other antiarrhythmic drugs.19

The most serious unwanted effect ispulmonary toxicity, which occurs in2% to 17% of patients and is observedwith doses higher than 300 mg daily.Between 2% and 10% of patients re-ceiving amiodarone have alterationsin thyroid function, and given the ar-rhythmogenic potential of thyrotoxi-cosis, can reverse the antiarrhythmiceffects of chronic amiodarone therapy(Table I).20

THE DISCOVERY OF SOTALOL

This compound was synthesized inabout 1960 by the Mead Johnson Com-pany, in Indiana, USA.21 It was one ofa series of analogs submitted to theUS Patent Office in January 1962, thepatent was subsequently abandonedand then refiled and finally completedin 1965. The patent made broad claimsincluding “vasopressors, vasodepres-sors, analgesics, bronchodilators, α-receptor stimulants, β-receptor stim-ulants, α-receptor blocking agents,β-receptor blocking agents, and papa-verine-like smooth muscle depres-sants.” DL-Sotalol was compound No. 11in this patent, but the preferred com-pound was No. 3, possessing “strongand selective adrenergic vasoconstric-tor emphasized activity.” Thus the β-blocking properties of sotalol (Com-pound 11) are not described in the ini-tial patent.22 Ironically, sotalol wouldhave been synthesized at the sametime as pronethalol and propranolol inthe ICI laboratories by Crowther andBlack (1958-1964), but sotalol’s poten-tial therapeutic utility was not initiallyrecognized, although eventually exten-sive clinical studies were undertaken.23

It was shown that sotalol had a moreattractive pharmacokinetic and phar-

macodynamic profile than propranolol.Unlike propranolol, it was not exten-sively metabolized and 80% was excret-ed unchanged in the urine while havinga half-life of about 10 hours comparedwith propranolol’s half-life of 2 hours.In addition, it had much less brain pen-etration. Perhaps more importantly, itdid not have significant “membrane-stabilizing properties” or quinidine-likeactions and had much less direct my-ocardial depressant properties.

The unique property of sotalol in pro-longing action potential duration in catpapillary muscle was first publishedby Kaumann and Olson in 1968.24 Theyshowed that sotalol (MJ1999) in a con-centration of 6�10-4 M lengthenedAPD from 401.3±46.4 ms (control) to1209.4±290 ms at 90% repolarization.In the conclusion of their paper, theyattribute its antifibrillatory propertiesin experimental canine infarction25 tothe fact that “It appears that the an-tifibrillatory activity of sotalol, unlikethat of other presently-known antiar-rhythmic agents, is attributable to themarked prolongation of the ventricu-lar action potential.”

In 1970, Singh and Vaughan Williamspublished their findings on the effectsof MJ1999 on the transmembrane ac-



Number Number affected Number Peto oddsof trials in amiodarone affected in ratio

Site of ADR reporting group placebo group (25% CI) P -value

Heart 6 98/2087 43/2066 2.40 (1.69, 3.41) <0.00001

Thyroid 5 74/2038 12/2014 4.19 (2.72, 6.45) <0.00001

Respiratory 6 76/2087 42/2066 1.78 (1.23, 2.58) 0.002

Nervous system 5 48/1782 19/1758 2.40 (1.48, 3.89) 0.0004

Liver 5 30/1782 14/1758 1.95 (1.07, 3.56) 0.03

Gastrointestinal tract 5 66/2038 47/2014 1.32 (0.9, 1.94) 0.15

Eyes 4 23/1702 6/1676 3.05 (1.46, 6.38) 0.003

Skin 6 24/2087 12/2066 1.93 (l.00, 3.72) 0.05

Table I. Meta-analysis of adverse effects of amiodarone in six randomized controlled trials.

Modified from reference 20: Loke YK, Derrey S, Aronson JK. A comparison of three different sources of data in assessing thefrequencies of adverse reactions to amiodarone. Br J Clin Pharmacol. 2004;57:616-621. Copyright © 2004, Blackwell Publishing.

tion potential in isolated ventricularand atrial muscle and confirmed thatit greatly prolonged the duration of theaction potential (Figure 1c).17 In theirdiscussion, they also made the pointthat “the main interest of the delay inrepolarization produced by MJ1999 isthat it is an immediate effect, appar-ent after a few minutes exposure tothe drug in vitro, whereas the effectproduced by thyroidectomy and amio-darone takes several weeks to devel-op.”1 Several years later it was shownthan sotalol prolonged the monopha-sic action potential duration in man,as well as an acute increase in effectiverefractory period.

In an elegant study, Creamer et al com-pared the effects of acute and chronicadministration of sotalol with thoseof propranolol in patients with pro-grammable pacemakers. Sotalol pro-longed the QT interval by 11.5% after1 month’s oral treatment, with a lessereffect of 6.5% following acute parenter-al administration. Propranolol did notcause any change in the QT interval.27

Extensive clinical studies with DL-so-

talol showed that it is effective in con-trolling both supraventricular and ven-tricular arrhythmias. The balance ofevidence suggested that the dual ef-fects of β-blockade (Class II) and pro-longation of APD (Class III) gave thebest clinical results.28 This may beimportant for the prevention of suddendeath in postinfarction patients, wherethe Class III agent D-sotalol was shownto be less effective than placebo.29 Itis not the purpose of this article toreview the comparative effectivenessof different classes of antiarrhythmicdrugs, but rather to describe the sub-sequent impact on cardiovascular re-search strategies within the pharma-ceutical industry of the initial discoveryof the selective specific prolongationof action potential duration (Class IIIdrugs).

SUBSEQUENTDEVELOPMENTS IN

CLASS III DRUG RESEARCH

The potential therapeutic utility of se-lective prolongation of APD was widelyrecognized.30 The perceived disadvan-

tages of amiodarone included poorbioavailability, complex pharmacolog-ical profile, and unacceptable side effects. Thus, research was directed to-ward finding patentable, potent, highlyselective Class III compounds. Therewere two assumptions underlying thisstrategy. Firstly, the beneficial antiar-rhythmic effects of amiodarone were at-tributed almost entirely to its Class IIIproperties and secondly, high specifici-ty for the major ion channel involvedin APD prolongation, namely, IKr, en-abled in vitro testing to proceed rapidly.

The research strategy was highly suc-cessful, in that at least 18 pharma-ceutical companies initiated researchprograms designed to discover im-proved Class III antiarrhythmic agents(Figures 2a and 2b, page 247 and248). Such programs would be domi-nated by medical chemistry conceptualskills, using one or more of the fouroriginal Class III chemical templates,namely, sotalol, isopropyl nitrophenyl-ethanolamine (INPEA), N-acetyl pro-cainamide (a metabolite of procainewith selective Class III actions), and

246



100 mV

0

100 V/s

dV/dt

0

CONTROL

SOTALOL (MJ1999)

RECOVERY

100 ms slow 100 ms

120 min washout 90 min washout

162�10-6 M (50 mg/L)—60 min exposure 324�10-8 M (100 mg/L)—80 min exposure

5 ms fast100 ms slow 100 ms5 ms fast

Figure 1c. The effect of sotalol (MJ1999) onintracellularly recordedpotentials of rabbit atria.

From reference 2:Vaughan Williams EM.Classification of anti-arrhythmic drugs. In:Sandoe E, Flensted-Jensen E, Olesen KH, eds.Symposium on CardiacArrhythmias. Sodertalje,Sweden: AB Astra; 1970:449-469. Copyright ©1970, Astra. All rightsreserved.

amiodarone. The majority of researchgroups synthesized chemical series inwhich the methanesulfonamidophenylgroup, present in sotalol, was retained(Figure 2b). For example, this substitu-tion in a structure based on N-acetylprocainamide (NAPA) resulted in thedevelopment of sematilide (Berlex).Similarly, Pfizer chemists prepared alarge chemical series based on thesotalol structure, resulting in 21 pub-lished patents and the development

of dofetilide (UK68798). The overall re-sult of this intense drug research activ-ity is somewhat limited in proportionto the enormous investment (Table II).

At present, the only Class III antiar-rhythmic drugs approved for parenteraland oral use are dofetilide (Pfizer), in-dicated for the conversion (parenteral)or maintenance (oral) of sinus rhythmin patients with atrial fibrillation. Asdofetilide also causes QT prolonga-tion and, in some instances, torsadesde pointes, treatment should be initi-ated in hospital, titrating the dose inrelation to both the QT interval andthe status of renal function.31

The other Class III compound is ibute-lide, approved only for parenteral usefor acute chemical conversion of atrialfibrillation or atrial flutter, as a possi-ble alternative to DC cardioversion. Inaddition to blocking the IKr channel,it activates a sustained sodium chan-nel, which must be distinguished fromthe “fast” sodium channel.32

There are three other Class III agentsin phase 3 clinical trials: tedesamil,azimilide, and dronedarone, none ofwhich block solely the IKr channel.

At this point, it is perhaps worth re-flecting how advances in the under-standing of the molecular mechanismsunderlying the genesis of the cardiacaction potential have influenced theapproach to devising improved anti-arrhythmic agents. In the context of

prolonging APD in order to prolongthe refractory period, at least sevenpotassium channels may play a role(Table III, page 249).33 A further dif-ficulty for “pure” IKr blockers is thatthe prolongation of APD induced bythem is reduced at rapid heart rates,a clinical situation that often requiresefficacy in antiarrhythmic therapy athigh heart rates. This phenomenon istermed “reverse use dependence.”34

An additional disadvantage of theirgreater blocking efficacy at slow heartrates is that excess APD prolongationmay trigger early afterdepolarizations,possibly leading to torsades de pointes.It is now apparent that the voltage-gated “delayed rectifier” potassiumcurrent (IK) is composed of two differ-ent currents carried by different ionchannel species, namely, the “slow”component IKs comprising a majorsubunit (KCNQ1) and a minor unit(KCNE1). The rapid component (IKr)is composed of the HERG (humanether-a-go-go-related gene) protein asthe major subunit and KCNE2 as theaccessory subunit. At high heart rates(high depolarization frequencies), theIKs outward current becomes the majorone and selective blockade of IKr haslittle effect on APD in this setting. Thechronic administration of amiodaronesignificantly decreases both IKr and IKs

so that the APD prolongation does notshow reverse use dependence. Thelower incidence of torsades de pointeson amiodarone therapy has been at-tributed to this dual action.

247



Cardiac Dose rangeDrug channel (mg) T1/2 (h) Excretion

Dofetilide IKr 0.125-0.5 PO bid 8 Kidney ≈80%

Sematilide IKr 100-150 PO tid 3-8 Kidney ≈75%

Ibutilide IKr slow Na current 0.5-2 IV 6 Liver

Azimilide IKr IKsr ICa(L) 100-125 PO od 100-120 Liver

Dronedarone IKr Ito IK(Ach) IKs ICa(L) 400 PO bid 150 Liver

Tedisamil Ito IKr 100 PO bid 16 Kidney

Table II. Cardiac and pharmacokinetic properties of newer “Class III” drugs.

Amiodarone

Dronedarone

H Cl

O

O

O

ON

l

l

l

l

ATl-2042

O

O

OO

ON

l

l

O

O O

NS

H

ON

E-047/1

O

O

S ON

KB-130015

O

ON

O

Figure 2a. Chemical structures of amiodaroneand benzofuran analogs.

It is perhaps ironical that potent bind-ing to the HERG protein in the IKr

channel is now perceived as a disad-vantageous property of Class III agentsbecause of proarrhythmia potential.Regulatory agencies now require dataon the effects of any novel compoundon the HERG channel prior to humanexposure. In retrospect, perhaps drugresearchers seeking an improved amio-darone were somewhat misled by as-suming that its major desirable prop-erty was prolongation of APD solelyby selective IKr blockade.

THE SEARCH FOR ANIMPROVED AMIODARONE

The cardiac channel actions of amio-darone include potent inhibition of theKr/Ks channels, moderate inhibitionof the cardiac α and β receptors, aswell as of the L-Ca channel and thefast sodium channel. The challenge in seeking an improvement on amio-darone is to decide how many of theseproperties contribute to its antiarrhyth-mic efficacy. Amiodarone is more effi-cacious than all other antiarrhythmic

drugs in treating atrial fibrillation, andis better than placebo or lidocaine fortreating ventricular fibrillation. The elec-trophysiological properties of acutelyadministered amiodarone are marked-ly different from those observed follow-ing chronic oral therapy, which resultsin APD prolongation. It is noteworthythat the original studies by Singh in-volved the study the effects of long-term intraperitoneal administration torabbits for prolonged periods followedby ex vivo studies on the atria andventricles. A single parenteral dose of

248



CH3SO2NH CNH2CH2CH2NC2H5

C2H5

O

Sematilide

CH3SO2NH

CH3SO2NH

C

O

O

O

E-4031

Azimilide

H2N C N

N

NH

HO

N CH2

CH2

NCH2

(CH2)4 CH3NN

O

Ambasilide

Terikalant

CH3SO2NH CH-(CH2)3NC2H5

(CH2)6CH3

OH

Ibutilide

NC OCH2 CH SCH2N(CH2)3 CH2CH2CH3

C2H5

OH

CHCl N

H

N

CN

NN

O

Almokalant

CH3SO2NH O(CH2)2N(CH2)2 NHSO2CH3

Dofetilide

L-706 000(MK-499)

CH3SO2NH CHCH2NCHCH3

OCH3

OCH3

CH3

CH3

CH3

OH

Sotalol

O

O

O

Figure 2b. Chemical structures of Class III agents based on the sotalol template.

amiodarone (5 mg/kg) causes only asignificant lengthening of the AH inter-val and atrioventricular nodal effectiverefractory period, with no effect on theheart rate or the QTc interval. There isthus a marked disparity between theelectrophysiological effects of acutelyadministered amiodarone and thoseobserved after long-term treatment(Table IV).35 The explanation for thesedifferences is not clearly understood,

but possibly the interaction of amio-darone (and its major metabolite desethylamiodarone) with thyroid hor-mones may be important.36 Amio-darone treatment causes a dose-de-pendent decrease in the expression ofseveral T3-dependent genes. The mainmetabolite, desethylamiodarone, in-hibits the binding of T3 to its nuclearreceptors. It is a competitive inhibitorat the α1 thyroid hormone receptor

(TRα1) and a noncompetitive inhibitorat the β1 thyroid hormone receptor(TRβ1). An additional complexity re-garding the mode of action of amio-darone is that the contribution of thesystemic and coronary vasodilator ac-tions of amiodarone to its overall anti-arrhythmic efficacy is not clearly estab-lished, though there is reason to believethat these effects are also beneficial.

The major shortcomings of amiodaronerelate, firstly, to its suboptimal phar-macokinetics properties. It is variablyabsorbed from the gut and is widelydistributed, accumulating in muscleand fat. It has an average half-life inhumans of 50 days, ranging between 20to 100 days. Its effects persist for up to1 month after stopping therapy. Sec-ondly, amiodarone treatment can beassociated with a range of adverse ef-fects involving multiple organ systems(Table II). These adverse events maybe due in part to the iodine content ofthe molecule (ie, changes in thyroidstatus and ocular deposits), but themechanism of the hepatic, skin, andpulmonary effects is not understood.20

Several research strategies have beenadopted in seeking agents with an effi-cacy similar to amiodarone, but withbetter tolerability and pharmacokinet-ics. Close analogs of amiodarone havebeen made by one group, preservingboth the benzofuran and di-iodo struc-tures, but substituting ester homologs,in order to achieve better kinetics andmore rapid onset of effect. The leadcompound (ATI 2042) is in phase 2 clin-ical trials. It has a half-life in humansof 100 hours instead of the 50-day half-life of amiodarone. Experimental stud-ies in isolated guinea pig hearts showthat ATI 2042 increases atrial conduc-tion time by 70% and APD and QTc by10%.37 It is not easy to understand thelogic of this group’s research strategybecause of the widespread assump-tion that the iodo substitution in amio-darone, which is also present in ATI2042, is a major contributor to its un-

249



Channel Selectivename Abbreviation Gene A-subunits blocker

Rapid delayed IKr KCNH2 ERG1 Class III (agents)rectifier

Slow delayed IKs KCMQI KVLQT (Mink) Class III (agents)rectifier

Inward rectifier IKi KCMJ4 KIR 2.3 Tertiapin (venom)

ATP-gated channel IK-ATPKCNJ8

KCNJ11KIR 6.1/6.2 ATP

Muscarinic IK-AchKCNJ3 KIR 3.1KCNJ5 KIR 3.4

Atropine

Transient outward Itol

KCND3 KV 2/4.2current JCNA4 KV 21.4

Ultrarapid delayed IKut ?

KV 1.5 (human)rectifier KV 1.3 (canine)

Table III. Selected voltage-gated cardiac potassium ion channels. K+ channels consist of pore-forming (�) transmembrane subunits and accessory units that can markedly alter the properties ofthe channel.

�

Electrophysiological parameter Acute Chronic

Increase in: RR interval ± +++*

PR interval ++ +++

QT/QTc ± ++++

AH interval ++ +++

QRS interval (rate-related) ++ +++

Atrial ERP + ++++

AV nodal ERP +++ ++++

Ventricular ERP ± ++++

His-Purkinje ERP ± +++

Bypass tracts (anterograde/retrograde) ± ++++

*Sympatholytic action.

Table IV. Comparison of the electrophysiological effects of acute versus chronic amiodaroneadministration in man.

Abbreviations: AV, atrioventricular; ERP, effective refractory period.

wanted side effects. The compoundKBI 30015, produced by Karo Bio AB(Sweden), also retains the benzofuranand di-iodo substitutions, but the hy-pothesis is that amiodarone’s actionon chronic administration is mediat-ed by inhibition of thyroid hormoneaction on the heart. KB1 30015 is anantagonist at both the human α andβ thyroid receptors (IC50 2.2 and 4.1micro, respectively.7 However, theelectrophysiological effects in acuteadministration studies show that itreduces the cardiac sodium and ICal

channels.38 It seems unlikely that theacute effects are due to modificationof thyroid hormone action on the heart.

An alternative strategy adopted by thescientists in the Sanofi laboratorieshad been to synthesize noniodinatedanalogs of amiodarone, preserving thebenzofuran structure. The most ad-vanced compound is dronedarone(SR 33589), which is in phase 3 clinicaltrials in atrial fibrillation.39 The litera-ture on the electrophysiological effectsof dronedarone provides differing pro-files, depending upon the animalspecies, whether the studies are invitro or in vivo or are acute or chronic.Specifically, its effects in prolongingAPD were not observed following acuteadministration to anesthetized dogs,but APD and QTc were significantlyprolonged following chronic treatment(2� 20 mg/kg/day) in a canine modelof atrioventricular block.40

While the electrophysiological prop-erties of dronedarone are not finallyagreed upon, the dose-ranging trial inatrial fibrillation (postconversion) in-dicates that in a dose of 800 mg/day,it increased the time to recurrence offibrillation from 5 days on placebo to60 days on therapy.39 Two additionalphase 3 clinical trials are in progress(EURIDIS [EURopean trial In atrial fib-rillation or flutter patients receivingDronedarone for the maIntenance ofSinus rhythm] and ADONIS [American-Australian-African trial with Drone-

darONe In atrial fibrillation or flutterpatients for the maintenance of Sinusrhythm), but the results are not cur-rently available. A trial of its antiar-rhythmic effects in moderate-to-severechronic heart failure (ANDROMEDA[ANtiarrhythmic trial with DROne-darone in Moderate to severe CHF Eval-uating morditity DecreAse]) showedan excess of deaths (24 vs 10) in thetreated group. The trial was stopped.On balance, it seems likely that drone-darone will be as effective as amio-darone, but its overall risk:benefit pro-file remains to be clearly established.

E-0471 is another analog of amio-darone in which the di-iodophenyl isreplaced by a thiophin. Studies inguinea pig myocytes show that it haseffects not only in depressing the IKr

channel, but also the slow and fastcomponents of the delayed rectifiercurrent as well as blocking the L-typeCa channel. An open pilot clinicalstudy showed beneficial effects in pa-tients with atrial arrhythmias.41,42

COMMENTARY

This essay has described the evolutionof the Class III antiarrhythmic drugsfrom their inception in the late 1960suntil the present time. The story illus-trates the continuing importance ofserendipity and clinical observationsin the drug discovery process. For ex-ample, sotalol was not originally syn-thesized as a β-blocker, but as part ofa structure/function study on the in-corporation of alkylsulfonamido groupsinto the benzene ring of phenylethanol-amines.21 The attractive properties ofDL-sotalol for arrhythmia control by aClass III action, as well as for treatingangina pectoris and hyperthyroidism,due to its β-blocking properties, wereentirely serendipitous observations.Similarly, the amiodarone researchprogram seeking an improved antiang-inal agent was based on the unsub-stantiated efficacy of khellin in anginapectoris.10 Its Class III actions were

only observed after chronic oral ad-ministration to rabbits, necessitatedby the poor solubility of amiodaronefor acute in vitro studies on cardiacelectrophysiology.4 Furthermore, thereversal of its effects on prolonging ac-tion potential duration in rabbit heartby coadministration of thyroxine, aswell as its slow onset of effect follow-ing oral dosing, are not fully explainedeven today.35 Its antiarrhythmic ef-fects were first detected in the clinicand only subsequently did the researchscientists in Labaz Laboratories studyits acute effects in experimental ar-rhythmias.15

The next phase of the Class III drugevolution was designed drug discovery,based on the reasonable assumptionthat potent, specific blockade of theIKr channel would provide improvedantiarrhythmic therapy. This target wasmade possible by the advances in elec-trophysiology and patch-clamp tech-nology. Furthermore, the availabilityD-sotalol as a chemical template, aswell as amiodarone, provided the me-dicinal chemists with ample opportu-nities. The currently approved Class IIIagents (dofetalide/ibutelide) are effec-tive in atrial arrhythmias, but are lesseffective in controlling serious ventric-ular arrhythmias.

Nevertheless, Class III agents are moreattractive than Class I and Class II because they have minimal negativehemodynamic effects and can be givenboth orally and parenterally.43 How-ever, potent highly selective blockadeof only the IKr channel with concomi-tant reverse use dependency can beassociated with potentially lethal tor-sades de pointes. The newer antiar-rhythmic agents, while termed Class III,have actions on one or more addition-al cardiac channels (see Table I), sothe research goals are moving awayfrom pure IKr blockade. Perhaps animportant lesson to be learned, withapplication to the whole field of drugdiscovery, is the pitfall of our tendency

250



to oversimplify the biological targets,in this case selective IKr blockade. Thisfield, like so many others in drug dis-covery, requires a deeper understand-ing of the complexity of biologicalsystems.44 Until this is more feasible,serendipity and translational research,both animal45 and human,46 will con-tinue to play a major role.

REFERENCES

1. Singh BN, Vaughan Williams EM.

A third class of anti-arrhythmic actions?Effects on atrial and ventricular intracellularpotentials and other pharmacological actionson cardiac muscle, of MJ1999 and AH3474.

Br J Pharmacol. 1970;39:675-689.

2. Vaughan Williams EM.

Classification of anti-arrhythmic drugs. In:Sandoe E, Flensted-Jensen E, Olesen KH, eds.

Symposium on Cardiac Arrhythmias.Sodertalje, Sweden: AB Astra; 1970:449-469.

3. Singh BN, Vaughan Williams EM.

The effects of amiodarone, a new anti-anginal drug, on cardiac muscle.

Br J Pharmacol. 1970;39:657-667.

4. Singh BN.

Historical development of the concept ofcontrolling cardiac arrhythmias by length-ening repolarisation: particular reference tosotalol.

Am J Cardiol. 1990;65:3a-11a.

5. Singh BN.

Amiodarone and homogeneity of ventricularrepolarisation and refractoriness.

J Cardiovasc. Pharmacol Ther.1996;1:265-270.

6. Singh BN, ed.

Electropharmacology of Amiodarone.Mt Kisco, NY: Future Publishing Company;1988.

7. Carlsson B, Singh BN, Temciuc M,et al.

Synthesis and preliminary characterizationof a novel anti-arrhythmic compound (KB130015) with an improved toxicity profilecompared with amiodarone.

J Med Chem. 2002;45:623-630.

8. Charlier R.

Un nouveau dilatateur coronarien de syn-thèse : étude pharmacologique [A new syn-thetic coronary dilator: pharmacologicalstudy].

Acta Cardiol. 1959(suppl VII):1-60.

9. Deltour G, Binon F, Henaux F,Charlier R.

Recherches dans la série des benzofuranes.I–Benzofuranes possédant une activité coro-narodilatrice [Research into the benzofuranseries. I. Benzofuranes with coronary dilatoractivity].

Arch Int Pharmacodyn. 1961;131:84-106.

10. Anrep GV, Kenawy MR, BarsoumGS, Mizrahy G.

Ammi visnaga in the treatment of the angi-nal syndrome.

Br Heart J. 1946;8:171.

11. Greiner T, Gold H, McCattell K,et al.

A method for the evaluation of the effects ofdrugs on cardiac pain in patients with an-gina of effort.

Am J Med. 1950;9:143-155.

12. Martindale.

The Extra Pharmacopoeia. (Supplemen-tary drugs and other substances). 31sted. London, UK: Royal PharmaceuticalSociety; 1996:1718.

13. Vastesaeger M, Gillot P, Rasson G.

Étude clinique d’une nouvelle medicationanti-angoreuse [Clinical study of a newantianginal medication].

Acta Cardiol. 1967;122:473-500.

14. Barzin J, Freson A.

Essais cliniques de l’amiodarone dans lesaffections coronariennes [Clinical trial ofamiodarone in coronary diseases].

Brux Med. 1969;2:105-122.

15. Charlier R, Delnaunois G,Bauthier J, Deltour G.

Recherches dans la série des benzofuranes.XL. Proprietétés antiarythmiques de l’amio-darone [Research into the benzofuran series.XL. Antiarrhythmic properties of amio-darone].

Cardiologia. 1969;54:83-90.

16. Freedberg AS, Papp J, VaughanWilliams EM.

The effect of altered thyroid state on atrialintracellular potentials.

J Physiol Lond. 1970;207:357-370.

17. Charlier R.

Cardiac actions in the dog of a new antago-nist of adrenergic excitation which does notproduce competitive blockade of adrenoceptors.

Br J Pharmacol. 1970;39:668-674.

18. Weinberg BA, Miles WM, Klein LS,Bolander JE, et al.

Five-year follow-up of 589 patients treatedwith amiodarone.

Am Heart J. 1993;125:109-115.

19. Holnloser S, Klingenheben T,Singh BN.

Amiodarone-associated pro-arrhythmiceffects: a review with special reference totorsades de pointes tachycardia.

Ann Intern Med. 1994 121:529-536.

20. Loke YK, Derrey S, Aronson JK.

A comparison of three different sources ofdata in assessing the frequencies of adversereactions to amiodarone.

Br J Clin Pharmacol. 2004;57:616-621.

21. Larsen AA, Lish PM.

A new bio-isostere: alkyl sulphonamidophen-ethanolamines.

Nature. 1964;203:1283-1284.

22. Mead Johnson & Co.

US patent No. 3341584. 1965.

23. Snart AG, ed.

Advances in Beta-Adrenergic BlockingTherapy: Sotalol. London, UK: ExcerptaMedica. 1974(pt I-V):106.

251



24. Kaumann AJ, Olson CB.

Temporal relation between long-lasting after-contractions and action potentials in catpapillary muscles.

Science. 1968;161:293-295.

25. Kaumann A, Aramendia P.

Prevention of ventricular fibrillation inducedby coronary ligation.

J Pharmacol Exp Ther. 1968;164:326-332.

26. Echt DS, Berte LE, Clusin WT, et al.

Prolongation of the human cardiac mono-phasic action potential by sotalol.

Am J Cardiol. 1982;50:1082-1086.

27. Creamer JE, Nathan AW, ShennanA, Camm AJ.

Acute and chronic effects of sotalol andpropranolol on ventricular repolarizationusing constant-rate pacing.

Am J Cardiol. 1986;57:1092-1096.

28. Soyka LF, Wirtz C, SpangenbergRB.

Clinical safety profile of sotalol in patientswith arrhythmias.

Am J Cardiol. 1990;65:74a-81a.

29. No authors listed.

Effect of d-sotalol on mortality in patientswith left ventricular dysfunction after recentand remote myocardial infarction.

Lancet. 1996;348:7-12.

30. Podrid PJ.

Amiodarone: re-evaluation of an old drug.

Ann Intern Med. 1995;122: 689-700.

31. Tham TC, Maclennan BA, BrukeMT, et al.

Pharmacodynamics and pharmaco-kineticsof the Class III antiarrhythmic agentDofetilide (UK 68798) in humans.

J Cardiovasc Pharmacol. 1993;21:507-512.

32. Lee KS, Gibson JK.

Unique ionic mechanism of action of ibutelideon freshly isolated heart cells.

Circulation. 1995;92:2755-2757.

33. Janse MJ.

To prolong refractoriness or to delayconduction (or both)?

Eur Heart J. 1992;13(suppl F):14-18.

34. Hondeghan LM, Snyders DJ.

Class III anti-arrhythmic agents have a lotof potential but a long way to go. Reducedeffectiveness and dangers of reverse usedependence.

Circulation. 1990;81:686-690.

35. Singh BN.

Amiodarone: historical development andpharmacologic profile.

Am Heart J. 1983;106:788-797.

36. Baekker O, van Beeren HC,Wiersinga WN.

Desethylamiodarone is a non-competitiveinhibitor of the binding of thyroid hormoneto the thyroid hormone �1 receptor protein.

Endocrinology. 1994;134:1665-1670.

37. Morey TE, Seubert CH,Raatikinen MJ, et al.

Structure-activity relationships and electro-physiological effects of short-acting amio-darone homologs in guinea pig isolatedheart.

J Pharmacol Exp Ther. 2001;297:260-266.

38. Macianskiene R, Bito V,Raemakers L, et al.

Action potential changes associated with aslowed inactivation of cardiac voltage—gated sodium channels by KB 130015.

Br J Pharmacol. 2003;139:1469-1479.

39. Touboul T, Brugada J, Capucci A,et al.

Dronedarone for prevention of atrial fibril-lation: a dose-ranging study.

Eur Heart J. 2003;24:1481-1487.

40. Verdun SC, Vos MA, LeunissenHD, et al.

Evaluation of the acute electro-physiologicaleffects of intravenous dronedarone, an amio-darone-like agent, with special emphasis onventricular repolarisation and acquired tor-sade de pointes arrhythmias.


41. Domanovits H, Schillinger M,Lercher P, et al.

E 047/1: a new Class III anti-arrhythmicagent.


42. Gombotha H, Vincenzi N, Mahla E,et al.

First clinical experience with the rapid,short-acting amiodarone derivative E 047/1after cardiac surgery.

Eur J Anaesthesiol. 2002;19:23-31.

43. Camm HA, Yap YG.

What should we expect from the next gen-eration of anti-arrhythmic drugs?

J Cardiovasc Electrophysiol. 1999;10:307-319.

44. Black J.

Future perspectives in pharmaceuticalresearch.

Pharm Policy Law. 1999;1:85-92.

45. Rosen MR.

The real thing.

Circ Res. 2000;87:6-7.

46. Lindsay MA.

Target discovery.

Nat Rev Drug Discov. 2003;2:831-838.

252



his Clinical Perspective article outlines theclinical decisions and potential problems indiagnosis facing clinicians when a patientpresents with a possible family history of di-lated cardiomyopathy. Although diagnosis of

dilated cardiomyopathy by clinical examination, electro-cardiography, echocardiography, and angiography is rela-tively straightforward, family pedigree, noninvasive screen-ing of informed consenting relatives, and possibly geneticanalysis of affected subjects is required to accurately diag-nose familial dilated cardiomyopathy. The article describesbasic Mendelian and matrilinear law-driven methods forcharacterizing the disease by tracing the familial pedigreeto understand the pattern of inheritance: for example, whena father, son, and daughter are all affected, an autosomaldominant disorder would be suspected, and X-linked, orrecessive disease could be excluded. Similar familial for-mulae can be applied to diagnose autosomal dominant,recessive, and X-linked recessive disease. However, this isonly the first step in a genetic approach to the disease.The diagnosis of familial cardiomyopathy is only the startof a detailed, and sometimes frustrating, investigative path-way. The etiopathogenic background of the disorder canbe further dissected by examining a number of pertinentclinical signs.

In this article, Arbustini et al describe eight different phe-notypes, detailing the clinical scenarios and outlining thesteps necessary for their effective clinical and pathologicalidentification. In their explanation of the diagnoses, theauthors outline possible pitfalls in the methodology andthe numerous problems associated with precise samplingwhen dealing with inheritable disorders of this type. Thisarticle further suggests an important link between thephysician, the clinical staff, the pathology laboratory, andthe research groups specializing in these disorders, sincemuch of the diagnosis involves complex molecular inves-tigation and can involve family members in order to pre-cisely pinpoint the origins of the disease.

At present, though, it is recommended that information onpatients should not rely on molecular genetics, but rather

on established clinical examination, assessment of the fa-milial condition of the disease, identification of preclinicalsigns and asymptomatic patients, prevention of ventriculararrhythmias, and counseling.

Despite the fact that the knowledge on the molecular ge-netics of this disease is growing, the number of diagnosesthat can be provided to patients is still limited to a fewcardiomyopathies and rare general myopathies with heartinvolvement. The literature, currently, only contains a fewarticles about this subject and it is clear that major multi-center research projects are required if cardiologists are toplan properly for the prevention and eventual cure of fa-milial dilated cardiomyopathy.

The authors of this article conclude by suggesting that amajor scientific society, such as the European Society ofCardiology, should promote research in this field and pro-vide the information needed to plan for useful preventivecare strategies for dilated cardiomyopathy.

254


Summaries of Ten Seminal Papers - Faircloth and others

Familial dilated cardiomyopathy: from clinical presentation to molecular genetics

E. Arbustini, P. Morbini, A. Gavazzi, L. Tavazzi

Eur Heart J. 2000;21:1825-1832

T

After 15 years as world chess champion, Gary Kasparov is beaten by his

25-year-old protégé, Vladimir Kramnik;thousands march in Berlin in memory

of the 1938 anti-Jewish pogrom that presaged the Holocaust; and an alcoholic brew mixed

with methanol to make it stronger kills 126 Kenyans and leaves a further 500

requiring hospital treatment

2000



255

ne of the less frequently addressed issues inthe management of heart failure is the highreadmission rate to hospital after an initialinpatient episode. The authors quote a rateof readmission of up to 44% within 6 months

of discharge. Among the causes of this high rate are poorcompliance with medication and delays in seeking preven-tative care. This paper describes an intervention that teachespatients to understand their illness better and respondappropriately if deteriorating, with the aim of reducing thefrequency of readmissions.

Consecutive admissions to the study hospital were screenedfor the presence of heart failure according to clinical orradiological parameters. Eighty-eight patients were enrolledinto the study, and randomized to the study group or tothe control group of usual medical care. Five educationaldomains were addressed, patient knowledge of the illness,the relationship between medications and illness, the re-lationship between health behavior and illness, knowledgeof the early features of decompensation, and practicalitiesof obtaining necessary assistance. There were two phasesof the intervention. In the first, an interview was conductedby an experienced cardiac nurse shortly after hospital dis-charge to identify the level of the patients’ understandingof the above issues, thus providing a framework for futureeducation. The second phase involved phone calls, initiallyweekly, but of reducing frequency, down to monthly, dur-ing which the nurse could reinforce education in the areaspreviously described. This contact was maintained over 12 months. In neither stage was an attempt made to per-form extra clinical assessments, although, if appropriate,patients were advised to see their physician.

In comparing the study and control groups, the readmis-sion rates were 56.8% and 81.8%, respectively (relative risk0.69, P=0.01), and there was a similar reduction in the rateof multiple readmissions. A nonsignificant reduction inthe death rate was observed in the treatment group. TheKaplan-Meier curves representing time to all-cause admis-sion or death diverge early on, and the median times tosuch an event were 193 days in the treatment group and

126 days in the control cohort (relative risk 0.56, P=0.03).An estimate of the potential economic impact of this in-tervention was made, and although this intervention in-volves extra costs, these were heavily outweighed by thereduction in readmissions, with mean savings of nearly$7000 per patient.

The key difference between this intervention and other pre-viously described related strategies in the treatment ofheart failure is that previous such studies have involved amore intensive provision of medical supervision. It appearsthat patient education and empowerment produce levelsof benefit that approach those of more reactive programsof physician- or nurse-led therapeutic adjustment.

This study leaves some questions open. It is not clear howlong the support needs to continue, nor whether there isan ongoing benefit to patients beyond 1 year. However, itis clear that there are very significant gains in terms of pa-tient morbidity/mortality and cost savings, which are theresult of a straightforward education program. As such, itseems reasonable to conclude that such initiatives couldand should be introduced more widely, and form part ofthe standard management of patients hospitalized withheart failure.

O

Horror writer Stephen King announces he will retire when his contract expires after

the publication of five more books;Argentina appoints its fifth President in two weeks;

and US reporter Pearl disappears while investigating alleged shoe bomber Richard Reid’s

ties to Moslem fundamentalists in Pakistan

2002

Randomized trial of an education and support intervention to prevent readmission of patients with heart failure

H. M. Krumholz, J. Amatruda, G. L. Smith, J. A. Mattera, S. A. Roumanis, M. J. Radford,P. Crombie, V. Vaccarino

J Am Coll Cardiol. 2002;39:83-89



Long-term trends in the incidence of and survival with heart failure

D. Levy, S. Kenchaiah, M. G. Larson, E. J. Benjamin, M. J. Kupka, K. K. Ho, J. M. Murabito, R. S. Vasan

N Engl J Med. 2002;347:1397-1402

ver recent decades, there have been signifi-cant advances in the treatment of hyperten-sion, historically the leading cause of heartfailure. In addition, the treatment of heartfailure itself has witnessed major advances,

with numerous randomized trials indicating the medicationsthat reduce mortality. However, there has been a lack ofclear evidence that these benefits have been translated intoimprovements in outcomes in the “real world.” In this pa-per, temporal trends among the Framingham study popula-tion are examined with regard to incidence of and survivalwith heart failure. This allows a longitudinal examinationof these parameters over a 50-year period, with the inherentadvantage that, in the Framingham study, a uniform setof diagnostic criteria and assessment has been utilizedthroughout.

The study began in 1948 with the enrollment of all mem-bers of the Framingham population aged 28 to 62 years.This cohort has been evaluated at 2-yearly intervals, and,in 1971, the descendents and their spouses were also en-rolled, with reviews taking place slightly less frequently. The age-adjusted incidence of heart failure was higher atall times in males than females. In the former, the initialincidence was 627 per 100 000 person-years, compared with420/100 000. The authors found little change in the inci-dence of heart failure in men over the last 50 years, while ithas dropped by about one third in women. After control-ling for various other risk factors, the risk of death hasfallen by approximately one third over the same period in both sexes, with an overall trend of reduction in risk of death of 12% per decade (P for trend, 0.01 in men and0.02 in women). Nevertheless, this leaves heart failure asa significant public health problem, and it remains a dis-ease with a high mortality. The median 5-year survival ratein men in the 1990s was under 4 years, and in women itwas 6 years, an improvement over the 2 and 4 years, respec-tively, seen in the 1950s.

In addressing the disparity between the sexes, the authorssuggest that the falling incidence among women may re-late to hypertension as a more frequent etiological factor in

women, with ischemic heart disease more common amongmen. There has been success in targeting and treating hy-pertension, but improvements in the treatment of myocar-dial infarction may have increased the number of survivorswithout affecting the numbers surviving with impaired leftventricular function. This, the authors suggest, is becausethere are now more survivors with residual damage, whoare thus at risk of heart failure.

Three recent hospital-based studies of the mortality afterhospitalization with heart failure have shown more sub-stantial reductions in mortality than in this series. The au-thors highlight that in this study hospitalization was not a criterion for enrollment. They also suggest that hospital-based studies are open to a number of biases. Improvedtechnology may result in lead-time bias, by allowing diag-nosis at a less severe stage. The nature of diagnosis-basedreimbursements to hospitals may influence the nature andnumber of diagnoses made.

There were some limitations to this study, including thepredominance of whites among the subjects, meaning thatone may not necessarily extrapolate these results to otherracial groups. Patients in the Framingham Heart Study mayhave had better medical access than other patients, lead-ing to better outcomes. Despite these concerns, one mayconclude that the incidence of heart failure among womenhas decreased and that improved survival has occurred inboth sexes over the last 50 years.

O

A study on animal intelligence reveals thatCalifornian sea lions may have the best

memory of all nonhuman creatures; the Pope canonizes Opus Dei founder Josemaria Escrivá de Balaguer; and

a masked gunman in Queens, New York, shootsrun-DMC D. J. Jason Mizell aka Jam Master Jay

2002

256



257

onor organs required for heart transplanta-tion are in limited supply and for many pa-tients the wait for transplant surgery provestoo long, with fatal deterioration before or-gan availability. A treatment to help maintain

an adequate circulation is the use of a left ventricular as-sist device (LVAD). LVADs have previously been shown toreduce mortality and are thought to lead to reverse remod-eling of myocardial structure and function.

This article seeks to determine whether mechanically un-loading the failing human heart with an LVAD results in sig-nificant change in left ventricular gene expression usinggene microarray technology. Previous reports have lookedat the expression of particular genes in response to thistreatment and have lead to the understanding that thisuseful therapy can lead to significant changes in gene andprotein expression. However, using oligonucleotide micro-array technology, which can detect approximately 6800genes or novel clones with homology to known genes, theauthors were able to examine many more genetic pathways,thus gaining a greater insight into some of the molecularmechanisms that may be involved in LVAD-mediated myo-cardial recovery.

Statistical analysis of gene arrays from 6 male patients atthe time of LVAD placement and at myocardial explantationrevealed a large number of genes that were upregulated ordownregulated in response to treatment. Interestingly,further statistical analysis revealed a clear demarcation be-tween gene expression profiles pre-LVAD and post-LVAD,and also identified two distinct groups among the pre-LVADfailing hearts depending on their etiology, determined bothclinically and pathologically after explantation. In particular,the pre-LVAD patients with nonischemic, idiopathic dilatedcardiomyopathy had distinctly different myocardial geneexpression post-LVAD, whereas those patients exhibitingischemic cardiomyopathy had similar gene profiles bothpre-LVAD and post-LVAD. Examination of this phenomenonrevealed that out of the 900 or so genes whose expressionwas modified during the treatment, only 16 were sharedbetween these two groups. This underscores the divergent

baseline phenotypes and responses to LVAD-mediated re-verse remodeling that occur in ischemic and nonischemiccardiomyopathies.

In addition, genes determined to have been significantlyregulated were sorted according to their biological func-tion. Although the data obtained were not shown to bestatistically different, it is of interest that there was an en-hancement in the percentage of metabolic genes changedsignificantly following LVAD support, thus supporting theauthors’ hypothesis that LVAD enhances reverse myocardialremodeling.

This study demonstrates the ability to distinguish patients’LVAD status and heart failure etiology using oligonucleotidemicroarrays. The differential gene expression identified inthe study further demonstrates that phenotypic changesthat occur following LVAD support are associated with geno-typic changes in the form of significantly altered myocar-dial gene expression profiles. Importantly, in their closingremarks, the authors suggest that microarray technologymight be used to facilitate the prediction of an individualpatient’s response to LVAD therapy.

D

Islamic cleric sheik Abdel Majid al-Khoei, a prominent Shiite, is murdered at the Najaf

mosque a week after returning to Iraq from exile;scientists at the British Columbia Cancer Agency

decipher the SARS genome, demonstrating it to be a completely new coronavirus; and

the Rijksmuseum in Amsterdam is closed for an indefinite period after asbestos is found in the

building during a routine inspection

2003

Differential gene expression and genomic patient stratificationfollowing left ventricular assist device support

B. C. Blaxall, B. M. Tschannen-Moran, C. A. Milano, W. J. Koch

J Am Coll Cardiol. 2003;41:1096-1106

Scientists create a mule, named Idaho Gem, from a cell from a mule fetus and a horse egg;

the Old Man of the Mountain, a 700-ton granite formation, falls from its perch at New Hampshire’s

Franconia Notch; and the military regime in Burma announces that Aung San Suu Kyi and

other members of Burma’s National League for Democracy are in protective custody

2003



258

espite the introduction of many new thera-pies for the treatment of chronic heart failure,morbidity and mortality remain high. It isclear, however, that patients with this condi-tion form a heterogeneous group and various

strategies have been employed to distinguish betweenthose at different levels of risk. Many of these strategies usemeasures that have inherent limitations. Peak oxygen con-sumption is demanding to record, and most suited to usein the assessment of the stable, moderately effected patient.The New York Heart Association (NYHA) classification, basedon symptoms, is intrinsically subjective. Laboratory mark-ers such as neurohormonal peptides have been demon-strated to be of predictive value at a population level, buttheir role in guiding individual management is less clear.

In 1976, Forrester et al described 4 hemodynamic profilesbased on pulmonary artery (PA) catheterization parame-ters. These profiles segregated patients according to thepresence or absence of congestion (pulmonary capillarywedge pressure threshold of 18 mm Hg), and adequacy ofperfusion (cardiac index threshold 2.2 L/min/m2). Forrester’soriginal paper demonstrated that the prognosis of patientspost–acute myocardial infarction correlated with their sub-group. The hypothesis examined in Nohria’s paper is thata similar classification based on clinical examination mightbe useful in guiding management.

Of the 452 patients enrolled into the study, the majoritywere admitted with decompensation of heart failure (49%),but there were significant numbers admitted with arrhyth-mias, angina, and for heart transplantation evaluation. Pa-tients were categorized according to the presence of con-gestion and adequacy of perfusion. Congestion (wet) wasdefined by the presence of recent history of orthopnea, elevation of the jugular venous pressure, hepatojugular re-flux, peripheral edema, leftward radiation of the pulmonaryheart sounds, or a square-wave blood pressure responseto a Valsalva maneuver. Impaired perfusion (cold) was de-fined by the presence of a narrow proportional pulse pres-sure (pulse pressure/SBP <25%), pulsus alternans, symp-tomatic hypotension, cool extremities, or impaired cognitive

function. This defined 4 groups: dry-warm (A), wet-warm (B),wet-cold (C), and dry-cold (L). Follow-up was for at least12 months, with end points of time to death and the com-bined end point of time to death or heart transplantation.

There were clear and significant differences between thedifferent groups, (although group L was too small to allowstatistical analysis). Compared with group A, the hazardratios were 3.66 for group C (P<0.001) and 2.10 for group B(P<0.003). Further stratification of these groups using theNYHA classification showed that groups B and C tendedto co-segregate with classes III and IV. However, theseclinical profiles were independent predictors of mortality.In a subset of patients investigated using the PA catheter,there was good correlation with the clinical groups.

The authors propose that these profiles may aid in the se-lection of appropriate therapy, in the same way that thePA catheter does, although accepting that there are no datato support this strategy. For example, profile A (dry-warm)may be likely to tolerate the introduction and uptitration ofβ-blockers, whereas, in group B, one would not do this un-til the patient had stabilized and returned to group A, andin Group C, one might consider reduction or cessation ofsuch drugs. In addition, it is proposed that since these pro-files are independent predictors of outcome, they may proveuseful tools in the selection of patients for clinical trials.

D

Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure

A. Nohria, S. W. Tsang, J. C. Fang, E. F. Lewis, J. A. Jarcho, G. H. Mudge, L. W. Stevenson

J Am Coll Cardiol. 2003;41:1797-1804

Indian Prime Minister Atal Bihari Vajpayee restores civilian air travel between his country

and Pakistan in an effort to ease tensions; more than 800 000 French public workers stage

a 1-day strike to protest pension reforms; and Nepal confers honorary citizenship on

Sir Edmund Hillary to mark the golden jubilee of the first ascent of Mount Everest

2003



his paper describes the long-term outcomesof patients recruited into the Studies Of LeftVentricular Dysfunction (SOLVD). The originalstudy recruited patients with left ventricular(LV) dysfunction (ejection fraction ≤35%) and

compared outcomes on enalapril vs placebo in patientswith and without overt heart failure. Although short-termbenefits of angiotensin-converting enzyme (ACE) inhibitorsin the treatment of LV dysfunction had been observed, thelonger-term effects were unknown. Furthermore, it was un-clear whether such a benefit could be enhanced by initiat-ing treatment prior to the development of symptoms.

A total of roughly 7000 patients were entered into the treat-ment or prevention arm based on whether or not they werealready receiving heart failure therapy or had symptoms ofheart failure. All were randomized to enalapril or placebo,and followed for a mean duration of 3.2 years.

The prevention trial showed a relative risk reduction in thecombined end point of death or development of heart fail-ure of 29%, (P<0.001). There was no significant reductionin mortality alone in this asymptomatic group, whereas inthe treatment group, the death rate was reduced by 16%(P=0.0036). It was suggested that those treated with enala-pril for heart failure gained 0.4 years of life expectancy.

The current manuscript reviews the outcomes after 12 yearsof follow-up. Despite this long follow-up period, outcomeswere known in 99.8% of the original participants. In the pre-vention study, death occurred in 56.4% in the placebo group,compared with 50.9% in the enalapril group (P=0.001),with an increase in median survival from 10.3 to 11.1 years(P=0.05). Furthermore, the survival curves continued todiverge for the whole period even though patients were notnecessarily on their assigned study medication after theend of the trial. In the treatment study, the death rate wasslightly lower in the enalapril group than the placebo, butmost patients were dead (79.8% and 80.8%, respectively).The survival curves, though initially inevitably diverging,converged toward the end of follow-up, as shown by themedian survival (5.5 and 4.8 years, respectively). There were

no differences in survival among the prespecified subgroupsaccording to age, gender, ethnicity, cause of LV dysfunc-tion, hypertension, diabetes mellitus, and New York HeartAssociation class at baseline. The benefit was seen to begreater in those with lower ejection fractions.

This extension of the original study has shown a benefit inthe prevention arm, and suggests that 56 deaths could beprevented by the treatment of 1000 patients for 3 years. Itis noted that after the first phase of the trial, patients werein many cases started on ACE inhibitors, as recommendedby the trial committee, with a probable reduction in thedifference observed between treated and placebo groups.The reduction in mortality with enalapril is felt to be pos-sibly due to a reduction in the rate of nonfatal myocardialinfarction during the initial study, with subsequently re-duced risk of progression to heart failure. The authors dis-cuss the convergence of the survival curves in the treatmentgroup and offer a number of suggestions. There was a sig-nificant reduction in the number of cardiac deaths and asimilar excess of noncardiac deaths, so they postulate thatwhen cardiac death is prevented, there may be exposureto alternative competing causes of death.

The authors conclude that treatment for 4 years with enala-pril in all patients with LV dysfunction reduces the risk ofdeath over the long term

T

Effect of enalapril on 12-year survival and life expectancy inpatients with left ventricular systolic dysfunction: a follow-up study

P. Jong, S. Yusuf, M. F. Rousseau, S. A. Ahn, S. I. Bangdiwala

Lancet. 2003;361:1843-1848

259



260

bservation of elevated levels of tumor necro-sis factor (TNF) in heart failure led to inves-tigations into its possible role in the patho-physiology of the condition. A heart failurephenotype is seen when TNF is administered

to experimental animals and in transgenic animals thatoverexpress TNF. High levels of TNF have been observedin a number of disparate conditions, including ankylosingspondylitis, rheumatoid arthritis, and psoriasis. Etanerceptis a recombinant human TNF receptor that binds to soluble(circulating) TNF, causing functional inactivation by pre-venting the binding of TNF to cell surface receptors. Trialsof it in the inflammatory conditions mentioned above re-sulted in clinical improvements, leading to trials in heartfailure. Small studies suggested that there was a benefit interms of left ventricular function, and thus larger clinicaltrials were designed.

This paper reports on the combined results of two studiesdesigned to determine the effects on patients’ functionalcapacity and morbidity/mortality. The studies had similardesigns, differing mainly by geographical locality: RECOVERtook place in Europe, Australasia, and Israel, while RE-NAISSANCE was undertaken in North America. Patientswith ischemic or nonischemic heart failure graded betweenNew York Heart Association class II and IV, with ejectionfraction ≤30%, were assigned to receive placebo or etaner-cept 25 mg SC once, twice, or three times a week. Bothstudies were terminated early (RECOVER after 6 months;RENAISSANCE after 12 months), due to failure to demon-strate benefit. There was no evidence of an excess mortali-ty in the etanercept groups, but there was certainly no ben-efit. Among prespecified subgroups, no differences wereobserved in the effects of etanercept.

To offer some possible explanation for this apparent lackof benefit, the authors briefly discussed the possibility thatTNF is not important in the pathogenesis of heart failure,and the elevated levels are a consequence of heart failure,or of chance. Second, although the conditions describedabove have been seen to improve with anti-TNF therapy,others associated with elevated levels, including Crohn’s

disease and systemic sepsis, do not respond. This impliesthat there may be a more complicated network of cytokines,and the removal of a single component may be insufficientto result in benefit. This could be assessed by the mea-surement of TNF bioactivity, as well as the levels of othercirculating cytokines. This would also be useful in investi-gating whether the dose of antagonist was sufficient to neu-tralize the effects of TNF. The authors observed that amongthose patients who worsened, disproportionately repre-sented were the patients who had been exposed to etaner-cept for the longest duration. They wondered whether thereis an early period of benefit, as seen in the pilot studies,followed by a period where continuation of etanercept isdetrimental. This might be caused by a phenomenon where-by etanercept stabilizes a biologically active (trimeric) formof TNF and thus paradoxically acts as a TNF potentiator.The final possibility is that TNF might play a useful role inmaintaining cardiovascular stability, and prolonged block-ade might therefore be deleterious.

Infliximab is a monoclonal antibody to TNF, recently em-ployed in the Anti-TNF-α in Congestive Heart Failure (ATTACH) study. Circulating TNF was neutralized, and cell-bound TNF resulted in cell lysis. This study reported anincrease in death and heart failure hospitalization. Althoughinfliximab and etanercept act in different ways, there mustnow be concern over the targeting of TNF in this way. Fu-ture therapies are likely to be directed at other componentsof the inflammatory cascade, or at multiple components.

O

Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept WorldwideEvaluation (RENEWAL)

D. L. Mann, J. J. McMurray, M. Packer, K. Swedberg, J. S. Borer, W. S. Colucci, J. Dijan, H. Drexler, A. Feldman, L. Kober, et al

Circulation. 2004;109:1594-1602

The discovery of a cat buried with its owner in aNeolithic grave on Cyprus suggests domestication

of cats began at least 9500 years ago; the popular search engine “Google” announces

it will offer shares to the public in late 2004; andthe African National Congress wins South Africa’sgeneral election claiming about 70% of the vote

2004



261

Regenerative capacity of the myocardium: implications for treatment of heart failure

R. von Harsdorf, P. A. Poole-Wilson, R. Dietz

Lancet. 2004;363:1306-1313

his review article describes in some depth nov-el approaches to the management of heart fail-ure and discusses the rationale for, as well asthe limitations of, each treatment. Von Harsdorfet al introduce a fictitious, but clinically typi-

cal, patient: a 46-year-old man with a recent diagnosis ofacute myocardial infarction (MI). Having survived the acuteperiod of MI the patient has substantial irreversible myo-cardial damage and exhibits symptoms of heart failure dueto the remodeling process. This is characterized by struc-tural changes within the healthy area of the heart bothadjacent to, and remote from, the damaged area. The au-thors go on to describe possible options for the patient’streatment and outline four possible alternatives: conven-tional drug therapy; cardiomyocyte replication therapy;cloning of artificial organs, and organ regeneration viastem cells.

Drug therapy, referred to as the “dinosaur approach,” in-volves the use of pharmacological blockade of the com-pensatory systems increasing myocardial workload. Suchapproaches are known to prolong life in patients with heartfailure. However, such therapy is limited since it will notcure the patient, the myocardium will remain damaged,since mammalian hearts are not able to significantly re-generate lost tissue. Therefore, conventional therapy mayonly serve to prolong the inevitable progress of heart fail-ure. Leading on from this approach, the authors describea novel therapy by which the patient’s myocardial cells areencouraged regenerate and replace, or prevent the gener-ation of, scar tissue, thus avoiding long-term drug therapy.Although not currently available, the rationale behind thisconcept is well defined in the article. Modification of theadult myocyte cell cycle is possible in vitro; however, wedo not fully understand how an adult heart will cope withreintroduction of proliferative capacity. Moreover, controlof cardiomyocyte replication will present a bigger challengeto modern biotechnology.

Although cloning of human tissue is not yet possible forethical reasons, the concept of regenerating an immunolog-ically compatible organ from nuclei taken from a skin biop-

sy is also discussed. The “Dolly approach,” as it is termed,describes the concept of manufacturing a copy of the pa-tient’s heart around a biodegradable scaffold. Althoughthere is no evidence to support this process it is, at leasttheoretically, possible, but would require an intimate knowl-edge of cardiomyocyte differentiation, which is currentlyabsent. Akin to organ cloning, there is much controversysurrounding stem cell therapy. Stem cells have the innateability to transform into any cell type given the right envi-ronmental factors. The authors are cautious to expand onthe efficacy of this approach, as there have not been anylarge controlled studies using stem cells.

The authors suggest the use of cautious optimism when itcomes to the development of these new therapies: so muchmore needs to be known before carefully controlled clini-cal trials of any of these new therapies can be undertaken.

T

At least 10 bombs explode on four commuter trainsin Madrid during the rush hour, killing 191 peopleand wounding more than a thousand; in the biggest

expansion in its 55-year history, NATO formally admits seven new countries, from the former IronCurtain zone; and NASA announces that its robotexplorer Opportunity has detected signs that water

once covered rocks in a small crater on Mars

2004

Pakistani scientist Abdul Qadeer Khan admitspassing on nuclear weapon technology

to other countries; new Spanish Prime Minister José Luis Rodríguez Zapatero orders the recall

of all Spanish soldiers from Iraq; andNorth Korea’s reclusive leader, Kim Jong-Il, arrives

in Beijing for talks on his country’s future

2004

262



ardiac resynchronization therapy (CRT) is nowan accepted tool in the treatment of severeleft ventricular dysfunction. In this editorial,Breithardt et al explain that despite growinguse of this technique, there is evidence that

up to 30% of those treated fail to respond. The underlyingstrategy centers on reducing the contraction delay betweeneach ventricle and/or between regions of the left ventricle.There is evidence that both these forms of delay may beimportant. Improved synchrony is achieved by preexcita-tion of the late-activated regions through the implantationof left ventricular or biventricular pacing electrodes.

The authors explain that the tools used to select the pa-tients may be insufficiently precise to predict who will re-spond. In particular, it is those cardiac segments with themost delayed onset of contraction that need to be identi-fied. The ideal tool to achieve such identification remainsan area of controversy. Similarly, there is a lack of consen-sus as to whether intraventricular or interventricular dys-synchrony is more responsive to CRT.

The authors outline the criteria for selecting an ideal imag-ing technique that will determine clinically important ab-normalities in the timing of onset of regional ventricular ac-tive force development. Such a technique also would needto be easy to interpret, reproducible, and cost-effective. A high sampling rate is also critical, since the intervals re-sponsible for delay are extremely short. Currently, the tech-nique that best fulfills these criteria is echocardiography.A fundamental question is what degree of delay is sufficientto be labelled abnormal and likely to benefit from correc-tion. In addition, there are a number of methods for mea-suring this delay. Regional longitudinal systolic velocityprofiles may be obtained from all ventricular segments, butdo not indicate the regional contractility. The more noveltechniques of strain rate and strain estimation imagingreflect contractility better, although technology does notallow their application in thin walled segments.

The cardiac event to be used as the marker to determinedelay is clearly very significant. Some researchers advocate

the time-to-onset of regional systolic motion, whereas oth-ers propose the time-to-peak systolic motion, or measuretime to postsystolic events. The authors conclude that thefirst of these options is preferable, since the presence of aplateau in the velocity profile will create possible errors indetermining the exact time of peak systolic motion, and theearlier a parameter is measured within the cardiac cycle,the less prone it is to distortion introduced by alterationsin loading conditions or segmental interactions.

Once having determined the presence of dyssynchrony byselecting a reliable technique and an appropriate parame-ter to measure, the authors highlight further important po-tential pitfalls relating to the underlying pathophysiology.For example, resynchronization therapy may reduce post-systolic shortening (PSS). PSS occurs in left bundle branchblock due to delayed segment activation, an appropriatetarget for resynchronization. However, it may similarly oc-cur in the presence of ischemia, when it is a passive phe-nomenon, and there will be no response to CRT.

The authors conclude that echocardiography is fundamen-tal in the selection of patients suitable for this therapy. Thefirst line of selection requires an abnormal QRS duration,with echocardiographic confirmation of dyssynchrony. Themore precise evaluation requires the use of the modalitiesdiscussed above, but large controlled trials are requiredto determine which is the optimal technique.

C

Do we understand who benefits from resynchronisation therapy?

O. A. Breithardt, P. Claus, G. R. Sutherland

Eur Heart J. 2004;25:535-536

ypertrophic cardiomyopathy (HCM) was firstdescribed in 1869. Although initial researchfocused on the morphology of the disorder,as evidence for an inherited pattern emerged,the focus turned to genetic studies, culmi-

nating in the first culprit gene mutation in the β-myosinheavy chain coding sequence.

Many further mutations in genes encoding this and othercomponents of the contractile apparatus have since beendiscovered, suggesting that this is the unifying factor inthe disparate group of phenotypes that constitute HCM.Detailed research into genotype-phenotype correlationshas failed to demonstrate consistent associations.

HCM is uncommon in children, and although a number ofconditions cause a similar pattern of disease in adults, at-tempts to distinguish the two should be made. The charac-teristic hypertrophy of the septum may also extend toother parts of the left ventricular wall, and rarely the rightventricle, but not the right ventricle alone. The histologicalhallmark is myocyte disarray.

One of the difficulties with the management of this condi-tion is that there may be few symptoms, and these maybe nonspecific. Similarly, the examination may be unreveal-ing. A bisferious pulse indicates dynamic outflow obstruc-tion, which will be associated with a systolic flow murmur.Mitral regurgitation may also be evident, relating to theanterior movement of the mitral valve during systole.

The echocardiogram is the major diagnostic tool, and anywall segment with a thickness of more than 15 mm withoutan alternative explanation is diagnostic. In the nonblackpatient, it is unusual for such hypertrophy to occur due tohypertension unless this is severe. Another major diagnos-tic conundrum is the athlete with hypertrophy, in whom itmay be difficult to make a certain diagnosis, though in thisgroup, both ventricles are usually enlarged. Dynamic ob-struction may also be revealed using echocardiography.Further echocardiographic parameters are discussed, in-cluding diastolic assessment and tissue Doppler imaging.

The role of cardiac magnetic resonance imaging in clinicalpractice is generally similar to that of echocardiography.

Metabolic exercise testing usually reveals reduced peakoxygen consumption, while a premature lactic acidosismay be indicative of mitochondrial myopathy. Symptomsrelating to outflow tract obstruction may be treated withβ-blockers, or occasionally disopyramide or verapamil. Ifdrug therapy is unsuccessful, septal myectomy or septalalcohol ablation may be performed. The treatment of heartfailure in HCM mirrors that due to other causes and, asatrial fibrillation may cause significant deterioration inHCM, restoration of sinus rhythm is important. There is apredisposition to sudden death in HCM, thought to be dueto ventricular arrhythmia in most cases. Implantable car-dioverter-defibrillators may help to prevent such deaths,and should be offered to those at high risk. A major chal-lenge exists to detect these individuals in advance of afirst event. The major risk predictors include a family his-tory of sudden cardiac death, unexplained syncope, non-sustained ventricular tachycardia on Holter monitoring,severe hypertrophy (>30 mm), and a flat blood pressureresponse during upright exercise.

Finally, the article discusses the need for genetic counsel-ing and suggests that an ECG and echocardiogram shouldbe performed in first-degree relatives of affected individu-als, and that echocardiography should be repeated every5 years, because of the possibility of late-onset disease.

H

263



Hypertrophic cardiomyopathy

P. Elliott, W. J. McKenna

Lancet. 2004;363:1881-1891

The Cassini spacecraft inserts into orbit aroundSaturn and transmits detailed photographs of theplanet’s complex ring system; Mike Melvil pilots“SpaceShipOne” into space, becoming the first person to do so in a privately developed aircraft;

and dozens of Colombian coca farmers are killed by Marxist rebels

2004


ACC/AHA 2002 Guidelines update for the management A report of the American College of Cardiology/American Heart of patients with chronic stable angina. Association Task Force on Practice Guidelines.

www.acc.org; www.americanheart.org. Accessed 15 December 2004.

Arbustini E, Diegoli M, Fasani R, et al. Mitochondrial DNA mutations and mitochondrial abnormalities indilated cardiomyopathy.

Am J Pathol. 1998;153:1501-1510.

Arbustini E, Diegoli M, Morbini P, et al. Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy.

J Am Coll Cardiol. 2000;35:1760-1768.

Arbustini E, Gavazzi A, Merlini G. Fibril-forming proteins: the amyloidosis. New hopes for a disease that cardiologists must know.

Ital Heart J. 2002;3:590-597.

Arbustini E, Morbini P, Grasso M, et al. Restrictive cardiomyopathy, atrioventricular block, and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits.


Arbustini E, Morbini P, Pilotto A, et al. Familial dilated cardiomyopathy: from clinical presentation to molecular genetics.

Eur Heart J. 2000;21:1825-1832.

Arbustini E, Morbini P, Pilotto A, et al. Genetics of idiopathic dilated cardiomyopathy.

Herz. 2000;25:156-160.

Ariza A, Coll J, Fernandez-Figueras M, et al. Desmin myopathy: a multisystem disorder involving skeletal, cardiac and smooth muscle.

Hum Pathol. 1995;26:1032-1037.

Armstrong PW, Ezekowitz JA, McAlister FA. Anaemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onsetheart failure.

Circulation. 2003;107:223-225.

Baig KM, Goldman JH, Caforio ALP, et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease.


Bibliography of One Hundred Key Papersselected by Luigi Tavazzi, MD, FESC, FASC; Eloisa Arbustini, MD, FESC

Department of Cardiology - Policlinico S. Matteo - Institute of Care and Research (IRCCS) - Pavia - ITALY

265

Heart Failure

266


Bibliography of One Hundred Key Papers

Bigger TJ, for the Coronary Artery Bypass Graft Patch Prophylactic use of implanted cardiac defibrillators in patients at Trial Investigators. high risk for ventricular arrhythmias after coronary artery bypass

graft surgery. CAPRICORN trial.

N Engl J Med. 1997;337:1569-1575.

Blaxal BC, Tschannen-Moran BM, Milano CA. Differential gene expression and genomic patient stratification following left ventricular assist device support.

J Am Coll Cardiol. 2003;41:1096-1106.

Bouvy ML, Heerdink ER, Leufkens HGM, et al. Predicting mortality in patients with heart failure: pragmatic approach.

Heart. 2003;89:1255-1264.

Brancaccio M, Fratta L, Notte A, et al. Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload.

Nat Med. 2003;9:68-75.

Breithardt OA, Claus P, Sutherland GR. Do we understand who benefits from resynchronisation therapy?

Eur Heart J. 2004 ;25:535-536.

Brenner BM, Cooper M, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patientswith type 2 diabetes and nephropathy. (RENAAL trial.)

N Engl J Med. 2001;345: 861-869.

Bristow MR, Saxon LA, Boehmer J, et al. Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.

N Engl J Med. 2004;350:2140-2150.

Cesari M, Penninx B, Newman A, et al. Inflammatory markers and onset of cardiovascular events. Results from the health ABC study.

Circulation. 2003;108:2317-2322.

Cleland JGF, Thygesen K, Uretsky BF, et al. Cardiovascular critical event pathways for the progression of heart failure.

Eur Heart J. 2001;22:1601-1612.

Cohn JN, Tognoni G, for the Valsartan Heart Failure A randomised trial of the angiotensin-receptor blocker valsartan Trial Investigators. in chronic heart failure.

N Engl J Med. 2001;345:1667-1675.

Corrà U, Mezzani A, Bosimini E, et al. Ventilatory response to exercise improves risk stratification in patientswith chronic heart failure and intermediate functional capacity.

Am Heart J. 2002;143:418-426.

Cowburn PJ, Cleland JGF, Coats AJ, et al. Risk stratification in chronic heart failure.

Eur Heart J. 1998;19:696-710.

Crispell KA, Hanson EL, Coates K, et al. Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy.

J Am Coll Cardiol. 2002;39:1503-1507.

Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan InterventionFor Endpoint reduction in hypertension study (LIFE): a randomisedtrial against atenolol.

Lancet. 1998;27:808-813.

267



Deswal A, Misra A, Bozkurt B. The role of anti-cytokine therapy in the failing heart.

Heart Fail Rev. 2001;61:143-151.

Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymtompatic and symptomatic patients with left ventricular systolic dysfunction.

J Am Coll Cardiol. 2000;102:681-689.

Duncan A, Wait D, Gibson D, et al. Left ventricular remodelling and haemodynamic effects of multisitebiventricular pacing in patients with left ventricular systolic dys-function and activation disturbances in sinus rhythm: sub-study of the MUSTIC trial.

Eur Heart J. 2003;24:430-431.

Eichhorn EJ. Prognosis determination in heart failure.

Am Heart J. 2001:110(suppl 7A):14S-35S.

Elliott P, McKenna WJ. Hypertrophic cardiomyopathy.

Lancet. 2004;363:1881-1891.

Felker M, Benza RL, Chandler B, et al, for the OPTIME Heart failure etiology and response to milrinone in decompensated Investigators. heart failure.

J Am Coll Cardiol. 2003;41:997-1003.

Felker MG, Shaw LK, O'Connor CM. A standardized definition of ischemic cardiomyopathy for use in clinical research.


Follath F, Cleland JGF, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.

Lancet. 2002;360:196-202.

Fox KM and the EUropean trial on Reduction Of cardiac Efficacy of perindopril in reduction of cardiovascular events amongevents with Perindopril in stable coronary Artery patients with stable coronary artery disease: randomized, double-disease Investigators. blind, placebo–controlled, multicentre trial (the EUROPA trial).

Lancet. 2003;362:782-788.

Franz WM, Muller OJ, Katus HA. Cardiomyopathies: from genetics to the prospect of treatment.

Lancet. 2001;358:1627-1637.

Gavazzi A, Repetto A, Scelsi L, et al. Evidence-based diagnosis of familial non X-linked dilated cardio-myopathy. Prevalence, inheritance and characteristics.

Eur Heart J. 2001;22:73-81.

Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular sys-tolic function and pulmonary artery pressure in patients with chronic heart failure.


GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Preven-zione trial.

Lancet. 1999;354:447-455.

Goldfarb LG, Vicart P, Goebel HH, et al. Desmin myopathy.

Brain. 2004;127:723-734.

268



Grigioni F, Barbieri, A, Magnani G, et al. Serial versus isolated assessment of clinical and instrumental parameters in heart failure: prognostic and therapeutic implications.

Am Heart J. 2003;146:298-303.

Gustaffson F, Torp-Pedersen C, Brendorp B, et al. Long-term survival in patients hospitalised with congestive heart fail-ure: relation to preserved and reduced left ventricular systolic function.

Eur Heart J. 2004;24:863-870.

Horwich TB, Fonarow GC, Hamilton MA, et al. Anaemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure.

J Am Coll Cardiol. 2002;39:1780-1786.

Huikuri V, Makikallio TH, Raatikainen P, et al. Prediction of sudden cardiac death. Appraisal of the studies and methods assessing the risk of sudden arrhythmic death.

Circulation. 2003;108:110-115.

Jong P, Yusuf S, Rousseau MF. Effect of enalapril on 12-year survival and life expectancy inpatientswith left ventricular systolic dysfunction: a follow-up study.

Lancet. 2003;361:1843-1848.

Kadish A, Dyer A, Daubert J, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.

N Engl J Med. 2004;350:2151-2158.

Kearney MT, Fox KA, Lee AJ, et al. Predicting death due to progressive heart failure in patients with mild to moderate chronic heart failure.

J Am Coll Cardiol. 2002;40:1801-1808.

Keller DI, Carrier L, Schwartz K. Genetics of familial cardiomyopathies and arrhythmias.

Swiss Med Wkly. 2002;132:401-407.

Koukkunen H, Penttila K, Kempaninen A, et al. C-reactive protein, fibrinogen, interleukin-6 and tumor necrosis fac-tor–alpha in the prognostic classification of unstable angina pectoris.

Ann Intern Med. 2001;33:37-47.

Krumholtz HM, Amatruda J, Smith GL, et al. Randomized trial of an education and support intervention to preventreadmission of patients with heart failure.


La Rovere MT, Pinna GD, Maestri R, et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients.

Circulation. 2003;107:565-570.

Levy D, Kenchaina S, Larson M, et al. Long-term trends in the incidence of and survival with heart failure.

N Engl J Med. 2002;18;1397-1402.

Maass AH, Leinwand LA. Mechanisms of the pathogenesis of troponin T-based familial hypertrophic cardiomyopathy.

Trends Cardiovasc Med. 2003;13:232-237.

Maggioni AP, Sinagra G, Opasich C, et al. Beta-blockers in patients with congestive heart failure: guided use in clinical practice investigators. Treatment of chronic heart failure with beta-adrenergic blockade beyond controlled clinical trials: the BRING-UP experience.

Heart. 2003;89:299-305.

269

Mann DL, MC Murray JV, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure:results of the randomised etanercept worldwide evaluation (RENEWAL).

Circulation. 2004;109:1594-1602.

Maron BJ. Hypertrophic cardiomyopathy. A systematic review.

JAMA. 2002;287:1308-1320.

Masoudi FA, Krumholz HM. Polypharmacy and comorbidity in heart failure.

BMJ. 2003;327:513-514.

Mestroni L, Maisch B, McKenna WJ, et al. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and CapitalMobility Project on Familial Dilated Cardiomyopathy.

Eur Heart J. 1999;20:93-102.

Mezzani A, Corrà U, Bosimini E, et al. Contribution of peak respiratory exchange ratio to peak VO2 prog-nostic reliability in patients with chronic heart failure and severely reduced exercise capacity.

Am Heart J. 2003;145:1102-1107.

Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomised, placebo-controlled, double-blind study (RUSSLAN).

Eur Heart J. 2002;23:1422-1432.

Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myo-cardial infarction and reduced ejection fraction.

N Engl J Med. 2002;346;877-883.

Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the prospective randomized amlodipine survival evaluation (PRAISE).

J Am Coll Cardiol. 2003;41:1933-1939.

Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure.

J Am Coll Cardiol. 2003;41:1797-1804.

Oosterga M, Voors AA, Buikema H, et al. Angiotensin II formation in human vasculature after chronic ACE-inhibition: a prospective, randomised, placebo-controlled study. QUO VADIS Investigators.

Cardiovasc Drugs Ther. 2000;14:55-60.

Opasich C, Pinna GD, Bobbio M, et al. Peak oxygen consumption in chronic heart failure: toward efficientuse in the individual patient.


Opasich C, Pinna GD, Mazza A, e al. Reproducibility of the six-minute walking test in patients with chronic congestive heart failure: practical implications.

Am J Cardiol. 1998;81:1497-1500.

Packer M. The neurohormonal hypothesis. A theory to explain the mechanism of disease progression in heart failure.




270



Pasotti M, Repetto A, Pisani A, et al. Diseases associated with lamin A/C gene defects: what the clinical cardiologist ought to know.

Ital Heart J Suppl. 2004;5:98-111.

Pepine CJ, Rouleau JL, Annis K, et al. Effects of angiotensin-converting enzyme inhibition on transient ischemia: the quinapril anti-ischemia and symptoms of angina reduction (QUASAR trial).

J Am Coll Cardiol. 2003;42:2049-2059.

Pfeffer MA, Mc Murray JV, Velasquez EJ, et al. Valsartan, Captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. VALIANT trial.

N Engl J Med. 2003;349:1893-1906.

Ponikowski P, Francis Darrel, Piepoli M, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance.

Circulation. 2002;103:967-976.

Salukhe T, Dimopoulos K, Sutton R, et al. Life-years gained from defibrillator implantation. Markedly non-linear increase during 3 years of follow-up and its implications.

Circulation. 2004;109:1848-1853.

Schaufelberger M, Swedberg K, Köster M, et al. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden: data from the Swedish Hospital Discharge Registry 1988 to 2000.

Eur Heart J. 2004;25:300-307.

Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant conges-tive heart failure using subcutaneous erythropoietin and intra-venous iron: a randomized controlled study.

J Am Coll Cardiol. 2001;37:1775-1780.

Smith G, Masoundi FS, Vaccarino V, et al. Outcomes in heart failure patients with preserved ejection fraction.

J Am Coll Cardiol. 2003;41:1510-1518.

Staessen JA, Fagard R, Thijs L, et al. Randomized double-blind comparison of placebo and active treat-ment for older patients with isolated systolic hypertension. (SYST-EUR trial).

Lancet. 1997;350:757-764.

Stevenson LW. Clinical use of inotropic therapy for heart failure: looking backwardor forward? Part I: Inotropic infusions during hospitalization.

Circulation. 2003;108:367-372.

Stewart S, Blue L, Walker A, et al. An economic analysis of specialists heart failure nurse managementin the UK: can we afford not to implement it?

Eur Heart J. 2002;23:1369-1378.

Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based intervention on unplannedreadmission and survival among patients with chronic congestive heart failure: a randomised controlled study.

Lancet. 1999;354:1077-1083.

Strömberg A, Martensson J, Fridlund B, et al. Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure.

Eur Heart J. 2003;24:1014-1023.

271

Swedberg K, Kjekshus J, Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril: ten years follow-up of CONSENSUS I.

Eur Heart J. 1999;20:136-139.

Tavazzi L, Tognoni G, Franzosi MG, et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvas-tatin in symptomatic congestive heart failure.

Eur J Heart Fail. 2004;6:635-641.

Tesson F, Sylvius N, Pilotto A, et al. Epidemiology of desmin and cardiac actin gene mutations in a European population of dilated cardiomyopathy.

Eur Heart J. 2000;21:1872-1876.

The ALLHAT Collaborative Research Group. The ALLHAT Officers and Coordinators for the ALLHAT CollaborativeResearch Group. Major outcomes in high-risk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial).

JAMA. 2002;288:2981-2997.

The AVID Investigators. The antiarrhythmics versus implantable defibrillators.

N Engl J Med. 1997;337:1576-1583.

The Heart Outcomes Prevention Evaluation Study Effect of an angiotensin–converting-enzyme inhibitor, ramipril, on Investigators. cardiovascular events in high-risk patients.(HOPE trial).

N Engl J Med. 2000;342:145-153.

Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham heart study.

Circulation. 2003;107:1486-1491.

Verrier RL, Tolath AV, Josephson ME. T-wave alternans for arrhythmia risk stratification in patients with idiopathic dilated cardiomyopathy.

J Am Coll Cardiol. 2003;14:2225-2227.

Von Harsdorf R, Poole-Wilson P, Dietz R. Regenerative capacity of the myocardium: implications for treatmentof heart failure.

Lancet. 2004;363:1306-1313.

Weingarten SR, Henninh JM, Badamgarav E, et al. Interventions used in disease management programmes for patientswith chronic illness—which ones work? Meta-analysis of publishedreports.

BMJ. 2002;325:1-8.

Whang W, Mittleman M, Rich DQ, et al. Heart failure and the risks of shocks in patients with implantable cardioverter defibrillators. Results from the triggers of ventricular arrhythmias (TOVA) study.

Circulation. 2004;109:1368-1391.

Working Group on Cardiac Rehabilitation and Exercise Recommendations for exercise testing in chronic heart failure Physiology and Working Group on Heart Failure of the patients. European Society of Cardiology. Eur Heart J. 2001;22:37-45.

Wright SP, Walsh H, Ingley KM, et al. Uptake of self-management strategies in a heart failure manage-ment programme.

Eur J Heart Fail. 2003;5:371-380.



Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversiondefibrillation in advanced chronic heart failure: the MIRACLE ICD trial.

JAMA. 2003;289:2685-2694.

Yusuf S, Pferrer M, Swedberg M, et al. Effect of candesartan in patients with chronic heart failure and preserved left-ventricular ejection: the CHARM-Preserved trial.

Lancet. 2003;362:777-781.

Zile MR. Heart failure with preserved ejection fraction: is this diastolic heart failure?

J Am Coll Cardiol. 2003;41:1519-1522.

272



Date post:	13-Mar-2020
Category:	Documents
Upload:	others
View:	2 times
Download:	0 times

Heart Failure · a major pathophysiological role in heart failure. Alhough these systems provide...

Documents