2000;84:106–112

CARDIOMYOPATHY Causes of dilated Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from Young Diagnosis and management of dilated x (infective/toxic/immune) cardiomyopathy x Carnitine deficiency 106 Perry Elliott x Selenium deficiency Department of Cardiological Sciences, x Anomalous coronary arteries St George’s Hospital Medical School, London, UK x Arteriovenous malformations x Kawasaki disease ilated cardiomyopathy is a heart mus- x Endocardial fibroelastosis cle disorder defined by the presence of Da dilated and poorly functioning left x Non-compacted myocardium ventricle in the absence of abnormal loading x Calcium deficiency conditions (, valve disease) or ischaemic heart disease suYcient to cause glo- x Familial IDC bal systolic impairment. A large number of cardiac and systemic diseases can cause systo- x lic impairment and left ventricular dilatation, Adolescent/adults but in the majority of patients no identifiable cause is found—hence the term “idiopathic” x Familial IDC dilated cardiomyopathy (IDC). There are experimental and clinical data in animals and x X linked humans suggesting that genetic, viral, and x immune factors contribute to the pathophysi- ology of IDC. x Myocarditis (infective/toxic/immune) x Tachycardiomyopathy Diagnosis x Mitochondrial

Clinical presentation x Arrhythmogenic right ventricular The first presentation of IDC may be with cardiomyopathy http://heart.bmj.com/ systemic embolism or sudden death, but x Eosinophilic (Churg Strauss syndrome) patients more typically present with of pulmonary congestion and/or x Drugs—anthracyclines low , often on a background of Peripartum exertional symptoms and fatigue for many x months or years before their diagnosis. Inter- x Endocrine current illness or the development of arrhyth- mia, in particular atrial fibrillation, may x Nutritional—thiamine, carnitine precipitate acute decompensation in such deficiency, hypophosphataemia, on September 29, 2021 by guest. Protected copyright. individuals. Increasingly, IDC is diagnosed hypocalcaemia incidentally in asymptomatic individuals during routine medical screening or family evaluation of patients with established diagnosis. family history, specific attention should be A careful family history facilitates diagnosis given to a history of , of inherited causes of IDC by characterising features of (for exam- the family phenotype, and also defines the ple, familial diabetes, deafness, epilepsy, ma- 1 scope of family screening. At least 25% of ternal inheritance), and signs and symptoms patients have evidence for familial disease with of other inherited metabolic diseases. Inborn predominantly autosomal dominant inherit- errors of usually present in ance. Clinically, familial disease is defined by infancy and childhood, but some may present the presence of two or more aVected indivi- in adulthood, in particular haemochromatosis. duals in a single family and should also be Nutritional deficiencies and endocrine abnor- suspected in all patients with IDC and a family history of premature cardiac death or conduc- malities may produce , and a tion system disease. A further 20% of relatives complete drug history is essential, both in Correspondence to: relation to the administration of cardiotoxic Dr PM Elliott, have isolated left ventricular enlargement that Department of can progress to IDC in a minority of cases. drugs such as anthracyclines and with respect Cardiological Dilated cardiomyopathy can occur in a to the use of illegal substances. abuse, Sciences, St George’s number of X linked diseases such as Becker’s in particular, can produce a chronic IDC Hospital Medical and Duchenne’s muscular dystrophies and X picture as well as an acute cardiomyopathy. School, Cranmer Exposure to HIV and other infectious agents Terrace, London linked IDC. It may also occur in patients with SW17 0RE, UK mitochondrial DNA and inherited such as hepatitis C may be relevant in some email:[email protected] metabolic disorders. Thus when taking a patients. Education in Heart

Electrocardiography The ECG in patients with IDC may be Diagnostic criteria for IDC

remarkably normal, but abnormalities ranging < 0.45 and/or a fractional Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from from isolated changes to septal Q waves shortening of < 25%, and a left ventricular end in patients with extensive left ventricular fibro- diastolic dimension of > 112% predicted value sis, prolongation of atrioventricular (AV) con- corrected for age and body surface area. duction, and may be observed. Sinus and supraven- Exclusion criteria: 107 tricular are common, in particular x Absence of systemic hypertension atrial fibrillation. Approximately 20–30% of (> 160/100 mm Hg) patients have non-sustained ventricular tachy- cardia and a small number present with x (> 50% in one or sustained . more major branches)

Echocardiography x Chronic excess alcohol (> 40 g/day female, An echocardiogram is essential for the diagno- > 80 g/day male for more than five years sis of IDC (fig 1). In patients with poor echo after six month abstinence windows other imaging modalities such as radionuclide scans and magnetic resonance x Systemic disease known to cause IDC may be useful. Recently suggested echocardio- x Pericardial diseases graphic criteria for IDC are shown in the adja- cent box. When making the diagnosis of IDC it x Congenital heart disease is important to take into account sex and body size. The most widely applied criteria in family x Cor pulmonale studies are based on the Henry formulae, with a left ventricular cavity dimension of > 112% Key of predicted normal values used to define left The criteria for left ventricular enlargement ventricular enlargement and a shortening frac- are based on data of Henry et al (Circulation tion of < 25% defining abnormal systolic func- 1980;62:1054–61). A value of > 112% of pre- tion. These criteria have some limitations, in dicted represents 2 SDs from the mean particular the use of only short axis dimensions corrected for body surface area and age given and a relatively low specificity in young by the formula: patients, but they are practical and reproduc- (45.3 × (body surface area)1/3 − (0.03 × age) ible. Recent European guidelines have sug- − 7.2) ±12%. gested that when screening family members a Mestroni et al have suggested a more conserva- more conservative cut oV of > 117% of tive cut oV of > 117% (2 SDs + 5%) in order http://heart.bmj.com/ predicted values (2 SD plus 5%) should be to increase specificity for family studies.1 used in order to increase specificity.1 However, a value of 112% is probably just as predictive of disease if systolic function is also Exercise testing abnormal. Symptom limited upright exercise testing is of considerable value when assessing functional limitation in patients with IDC, particularly cated , coxsackie B, is ubiquitous in when combined with respiratory gas analysis. most communities and causes small subclinical Metabolic exercise testing provides an objec- epidemics. At present, the detection of viral on September 29, 2021 by guest. Protected copyright. tive measure of exercise capacity, facilitates antibodies in patients with stable chronic IDC assessment of disease progression, helps assess has little impact on management, but viral prognosis, and is useful in selecting patients for studies may become more important in the cardiac transplantation. Metabolic exercise future if current trials suggest a role for testing may also provide diagnostic infor- immunosuppressive/modulatory treatments in mation in patients with left ventricular impair- IDC. ment caused by primary metabolic abnormali- ties such as mitochondrial disease, by detecting Endomyocardial biopsy severe acidaemia. Although endomyocardial biopsy can be used to diagnose a wide range of myocardial Viral serology diseases, most are rare causes of IDC and can In children and adults with acute myocarditis, often be diagnosed by other means. Even the viral culture and serology may be useful in detection of an inflammatory cardiomyopathy establishing a diagnosis of viral myocarditis by is of limited use, given the uncertainties and demonstrating rising titres of neutralising anti- inconsistencies surrounding its diagnosis using bodies, or virus specific IgM class antibodies to conventional light microscope criteria. Endo- indicative of recent . In myocardial biopsy may be of use in selected adults with IDC the relation between viral patients—for example, those with suspected infection and disease is more uncertain. Many cardiac haemochromatosis and other infiltra- studies purporting to demonstrate a positive tive or malignant diseases—but in general it association between viral infection and IDC are should be confined to carefully conducted very small, and have failed to control for cross clinical trials. A number of immunohistological contamination with laboratory controls.2 The studies have already demonstrated increased source of disease and control populations is numbers of T cells and increased expression of also important as the most commonly impli- endothelial and interstitial MHC (major histo- Education in Heart Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from

108

Figure 2: Myocardial section from a patient with IDC stained for the intercellular adhesion molecule 1 (ICAM-1) (green) and factor VIII (red). Dual staining in yellow indicates the presence of endothelial ICAM activity, indicative of chronic low grade inflammation. Reproduced with permission from Professor Michael Davies.

Recommended tests in adult patients with IDC

x Erythrocyte sedimentation rate (ESR)

x Creatine kinase (CK)

x Viral serology (if acute presentation)

x Renal function

x Liver function tests/calcium

x Serum ferritin/iron/transferrin

x Thyroid function tests http://heart.bmj.com/

Only in specific indications:

x Coronary angiography Figure 1: Parasternal long axis (A) and apical four chamber (B) cross sectional (two dimensional) echocardiograms in a 23 year old patient with IDC. x – autoantibodies – carnitine

– lactate/pyruvate Treatment on September 29, 2021 by guest. Protected copyright. – selenium – pyruvate – acylcarnitine profile Specific treatments are not available for most – drug screen patients with IDC. Therefore, the primary – red cell transketolase (beri beri) aims of treatment are to control symptoms and – infective screen (HIV/hepatitis C, to prevent disease progression and complica- enteroviruses) tions such as progressive heart failure, sudden death, and thromboembolism. re- x Urine main central to the management of congestive – organic acid/amino acids symptoms, but they should not be used as monotherapy as they exacerbate neurohumoral x Skeletal muscle biopsy activation and may contribute to disease progression unless administered concomitantly Endomyocardial biopsy x with neurohumoral antagonists.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS Activation of the renin–angiotensin– compatibility complex) antigens and cell aldosterone system (RAAS) is central to the adhesion molecules in IDC , consistent pathophysiology of heart failure of whatever with previous observations of immune underlying aetiology. For this reason, angio- 3 activity in IDC (fig 2). As our understanding tensin converting enzyme (ACE) inhibitors are of the clinical significance of immunohisto- the mainstays of treatment in patients with chemical markers improves, it is likely that IDC, irrespective of the severity of heart endomyocardial biopsy will become more failure.4 ACE inhibitors improve dyspnoea and important in guiding immunomodulatory exercise tolerance, reduce hospitalisation rates, treatment. and reduce cardiovascular mortality. They also Education in Heart

prevent or slow disease progression in asymp- utes to progressive left ventricular dysfunction. tomatic patients. A substantial proportion of It has been recognised for some time that

patients who are given ACE inhibitors fail to excess sympathetic activity contributes to the Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from reach the target doses reported in randomised clinical syndrome of heart failure, but it was studies. Recent evidence from the ATLAS only recently that use of â blockers in heart study5 suggests that maximum recommended failure patients gained widespread acceptance. doses of lisinopril (32.5–35 mg) are as well tol- Three recent multicentre placebo controlled erated as low doses (2.5–5 mg), and are associ- studies, the US carvedilol studies,8 CIBIS II 109 ated with a 12% greater reduction in the com- (bisoprolol),9 and MERIT-HF (metoprolol),10 bined risk of death or hospitalisation. Although have demonstrated substantial reductions in the comparative benefit of intermediate doses sudden death and death from progressive heart is still uncertain, it seems prudent to try to failure in patients with predominantly New achieve recommended target doses in most York Heart Association (NYHA) class II and patients. III symptoms treated with â blockers. In CIBIS Significant side eVects are uncommon dur- II and MERIT-HF, but not the US carvedilol ing ACE inhibitor treatment, the most frequent study, subgroup analysis suggested a greater being hypotension, cough, and deterioration of eVect in patients with ischaemic heart failure renal function. Mild impairment of renal func- compared to “non-ischaemic” heart failure. tion (creatinine up to 265 µmol/l) in the Nevertheless, when taken together with earlier absence of renal artery stenosis is not, however, studies, these data suggest that it is advisable to an absolute contraindication for ACE inhibi- consider â blockers in IDC patients with mild tion. Similarly, a resting systolic pressure of to moderate symptoms in spite of maximal 80–90 mm Hg during treatment is acceptable treatment with ACE inhibitors. Patients should in the absence of postural symptoms. When not be started on â blockers if they have signs side eVects are problematic, the first step is to or symptoms of decompensated heart failure, consider reducing the dose of other medica- and initial doses should be low (carvedilol tions. In particular, doses can often be 3.125 mg twice daily, bisoprolol 1.25 mg once reduced in patients who no longer have daily, metoprolol SR 12.5 mg once daily). congestive symptoms. When ACE inhibitors Doses should be increased gradually every 2–4 have to be discontinued, hydralazine–nitrate weeks, monitoring closely for hypotension, combination can be useful in treating conges- or worsening heart failure until the tive symptoms. target dose is achieved or side eVects occur.

ANGIOTENSIN II RECEPTOR ANTAGONISTS SPIRONOLACTONE Angiotensin II (AII) receptor antagonists have High plasma concentrations of aldosterone are recently attracted much interest and contro- frequent in patients with moderate to severe http://heart.bmj.com/ versy with regard to their place in the heart heart failure and contribute to sodium reten- failure therapeutic armoury. AII receptor tion, potassium loss, sympathetic activation, antagonists have haemodynamic eVects myocardial fibrosis, and baroreceptor dysfunc- broadly similar to those of ACE inhibitors, but tion. ACE inhibition usually results in only a may be slightly better tolerated and at least transient decrease in aldosterone concentra- theoretically overcome the “escape” of angio- tions, probably because a major source of tensin system blockade observed in some aldosterone is reduced hepatic clearance rather patients on ACE inhibitors. However, unlike than angiotensin dependent adrenal secretion. ACE inhibitors, AII receptor antagonists do The recent RALES study11 has shown that the on September 29, 2021 by guest. Protected copyright. not inhibit bradykinin metabolism and thus addition of 25 mg of spironolactone to conven- lack a potentially beneficial vasodilatory eVect. tional treatment in patients with an ejection The ELITE-1 study6 suggested that losartan fraction < 35% and a history of NYHA class IV may have a greater eVect on mortality than heart failure is associated with a 30% reduction captopril in elderly patients with mild to mod- in the overall risk of death. Hospitalisation rates erate heart failure. Preliminary data from the for cardiac causes and functional status also follow up to this study have failed to demon- improved, and serious hyperkalaemia was strate a superior eVect of losartan over infrequent in patients with a serum creatinine captopril, but the study was not powered to < 221 µmol/l. The drug should be considered detect equivalence between the two drugs. The in all patients presenting with moderate to recent RESOLVD study7 has suggested that severe heart failure symptoms. combination treatment with an ACE inhibitor and an AII antagonist may be more beneficial in reducing neurohumoral activation and in Novel potential pharmacological preventing ventricular remodelling than either treatments drug alone. A number of trials (VALHEFT, CHARM) are currently addressing these and other issues regarding AII receptor treatment. NATRIURETIC PEPTIDES Atrial natriuretic peptide (ANP) is released  BLOCKERS from atrial myocytes in response to stretch, and In spite of ACE inhibitor treatment, mortality induces diuresis, naturesis, vasodilatation, and continues to be high in patients with heart fail- suppression of the renin–angiotensin system. ure. This is perhaps not surprising given that Circulating concentrations of ANP are in- ACE inhibitors act on only one aspect of the creased in congestive cardiac failure and corre- neurohumoral cascade (RAAS) that contrib- late with NYHA functional class and progno- Education in Heart

sis. Both ANP and brain natriuretic peptide are trials have evaluated amiodarone in IDC, but potent vasodilators and diuretics, but clinical only one, GESICA,14 has demonstrated an

trials have shown that tolerance frequently improvement in overall prognosis. The second Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from develops during intravenous ANP administra- study, CHF-STAT,15 did not demonstrate an tion. This problem may be overcome by the improvement in overall survival, but there was development of drugs that inhibit neutral a non-significant trend towards improved endopeptidase, the enzyme responsible for survival in patients with “non-ischaemic” 110 breakdown of natriuretic peptides. cardiomyopathy. Dofetilide,16 a more recently developed class III agent, has a neutral eVect CYTOKINE ANTAGONISTS on overall survival but does reduce the Tumour necrosis factor á (TNFá) or cachectin incidence of atrial fibrillation. These data sug- is a proinflammatory cytokine released from gest that class III agents can be safely used to activated macrophages, T cells, and failing treat or prevent symptomatic supraventricular myocardium. It circulates at high concentra- arrhythmias in IDC, but they cannot be tions in patients with congestive cardiac failure recommended for sudden death prophylaxis. and in experimental models causes pulmonary There are as yet no large scale randomised data oedema, cardiomyopathy, cachexia, and re- of implantable cardioverter defribrillator duced peripheral blood flow. Raised plasma (ICD) treatment in IDC, but it is reasonable to concentrations of TNFá and other proinflam- consider ICDs in patients with sustained matory cytokines such as interleukin 6 have haemodynamically unstable ventricular been interpreted as epiphenomena of heart tachycardia/fibrillation. The role of ICDs in failure, but it is increasingly thought that patients without symptomatic ventricular cytokines may promote heart failure progres- will hopefully be answered by sion. The experience with TNFá antagonists in ongoing trials (for example, SCD-HEFT). heart failure is limited, but there are intriguing data on pentoxyfilline, a xanthine derivative that suppresses TNFá production,12 and Non-pharmacological treatment of etanercept, a soluble P75 tumour necrosis advanced heart failure factor receptor that binds irreversibly with TNF .13 Etanercept is currently being á Heterotopic is still the evaluated in two large multicentre studies cornerstone of advanced heart failure manage- (RENAISSANCE and RECOVER). ment in patients with intractable heart failure Endothelins are another family of locally symptoms and end stage disease. However, acting peptides with profound vasoconstrictor transplantation remains limited by the scarcity eVects found in high plasma concentrations in of suitable organs and the development of graft

patients with heart failure. Experimental data http://heart.bmj.com/ vasculopathy. In response to this dilemma sev- using the endothelin antagonist bosentan have eral novel approaches are being evaluated. shown favourable haemodynamic eVects in heart failure patients, although the drug is associated with dose related hepatic dysfunc- PARTIAL LEFT VENTRICULECTOMY (“BATISTA” tion, prompting the investigation of more PROCEDURE) selective endothelin antagonists. Partial left ventriculectomy is based on the hypothesis that as wall tension is related to left ventricular diameter (Laplace’s law), reducing NTICOAGULANTS

A on September 29, 2021 by guest. Protected copyright. the left ventricular size by excision of a portion Although the annual risk of thromboembolism of its circumference should reduce wall stress in patients with IDC is relatively low, many and improve ventricular haemodynamics. In patients are young and are exposed to an the best centres results from this intervention appreciable cumulative risk of systemic emboli- were initially remarkably good given the nature sation. At present there are no trial data to of the procedure. It is clear, however, that even guide treatment in IDC, but with careful patient selection many patients warfarin is advised in patients with a history of survive only with the benefit of left ventricular thromboembolism or evidence of intracardiac assist devices and subsequent transplantation.17 thrombus. Patients with more than moderate Late sudden death is also described in a ventricular dilatation and moderate to severe proportion of survivors. The diYculties associ- systolic dysfunction should also be advised to ated with patient selection and subsequent take warfarin. postoperative care suggest that, at best, this form of treatment will be confined to a very small number of experienced centres. Management of arrhythmia in IDC

LEFT VENTRICULAR ASSIST DEVICES There are substantial limitations to most Left ventricular assist devices (LVADs) have currently available antiarrhythmic drugs in recently received approval from the US Food IDC, in particular their negative inotropic and and Drug Administration for use in patients proarrhythmic eVects. Evidence from studies with end stage heart failure as a bridge to car- showing increased mortality in patients with diac transplantation. Experience in patients advanced heart failure treated with class I with IDC suggests that LVAD treatment can agents suggest that these drugs should not be result in an apparent improvement in left ven- used to prevent arrhythmias of any origin in tricular function that may persist when the IDC except in an emergency. Two large scale device is removed. However, there are as yet no Education in Heart

reliable markers that distinguish the minority of patients that sustain useful recovery from the Trial acronyms

majority that deteriorate following explanta- ATLAS: Assessment of Treatment with Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from tion of the device. Technical advances in LVAD Lisinopril And Survival design now raise the possibility of using these CHARM: Candesartan in Heart Failure devices as an alternative to transplantation in Assessment of Reduction in Mortality and patients who are not transplant candidates. Morbidity This mode of treatment is currently being CHF-STAT: Congestive Heart Failure: 111 Survival Trial of Antiarrhythmic Therapy evaluated in the REMATCH study,18 which if positive will have substantial clinical and CIBIS: Cardiac InsuYciency Bisoprolol Study resource implications for centres managing advanced heart failure. ELITE: Evaluation of Losartan in the Elderly study GESICA: Grupo de Estudio de la MULTISITE VENTRICULAR PACING Sobrevida en la Insuficiencia Cardiaca en Many patients with advanced IDC have abnor- Argentina mal left ventricular activation that in turn MERIT-HF: Metoprolol CR/XL results in prolonged and incoordinate ventricu- Randomized Intervention Trial in Heart lar relaxation. In some patients ventricular Failure conduction delay is also associated with RALES: Randomized Aldactone Evaluation prolongation of atrioventricular conduction, Study resulting in a loss of atrioventricular synchrony RECOVER: Research into Etanercept: and a predisposition to prolonged functional Cytokine Antagonism in Ventricular mitral regurgitation. Dual chamber pacing has Dysfunction been advocated as a method for restoring AV REMATCH: Randomized Evaluation of synchrony and improving left ventricular coor- Mechanical Assistance Therapy as an Alternative in Congestive Heart Failure dination in patients with severe congestive heart failure. Although initially favourable RENAISSANCE: Randomized Enbrel North American Strategy to study haemodynamic results using conventional right Antagonism of Cytokines ventricular pacing were not confirmed by later RESOLVD: Randomized Evaluation of studies, there has been a more consistent Strategies for Left Ventricular Dysfunction response in studies that have used biventricular SCD-HEFT: Sudden Cardiac Death in pacing, the outcome depending critically on Heart Failure Trial the native QRS duration and the paced AV VALHEFT: Valsartan Heart Failure Trial delay.19 Patients should be considered for biventricular pacing if they have QRS duration http://heart.bmj.com/ greater than 150 ms, PR interval prolongation, and symptoms refractory to conventional The future medical treatment.

IDC is a disease of diverse causes and pathophysiology. Among the many challenges facing clinicians treating patients with the Immunomodulation/immunosuppression disorder are the detection of early disease, the on September 29, 2021 by guest. Protected copyright. identification of the predominant mechanism While there is considerable evidence to suggest of left ventricular dysfunction, and the develop- that plays a significant role in ment of treatments that target the initiating the pathophysiology of IDC, there has been lit- mechanism of disease. Nevertheless, there have tle evidence to suggest that immunosuppres- been major advances in our understanding of sive treatment is of any benefit. This lack of the genetic and immunological basis of IDC, response is, perhaps, not that surprising given and recent advances in the pharmacotherapy of the limitations of criteria used to select patients heart failure have substantially improved the for treatment in immunosuppresive studies and outlook for many patients. The rapid pace of the heterogeneity of the underlying aetiology of current research and the development of new treatments for the management of both early the condition. Immunosuppression is also a and late disease augur well for the future. rather indiscriminate weapon, as it may sup- press potentially beneficial immune responses 1. Mestroni L, Maisch B, McKenna WJ, et al. such as neutralising antibody production in Collaborative research group of the European human and capital mobility project on familial dilated cardiomyopathy. patients with chronic viral myocarditis. New Guidelines for the study of familial dilated . approaches to the diagnosis of chronic myocar- Eur Heart J 1999;20:93–102. • The inherited nature of IDC is often overlooked in the ditis and the treatment of inflammatory management of patients with IDC. This paper provides a cardiomyopathy should improve this situation. set of practical guidelines for the clinical diagnosis of There are already interesting preliminary data carriers. 20 2. Baboonian C, Treasure T. Meta-analysis of the suggesting that high dose immunoglobulin association of enteroviruses with human heart disease. and immunoadsorption may result in short Heart 1997;78:539–43. • This review discusses some of the potential reasons for term improvement in left ventricular perform- the wide range of estimates for viral infection in patients ance in patients with dilated and peripartum with IDC. In many cases methodological considerations are just as important as genuine variation in the incidence cardiomyopathy. of viral infection. Education in Heart

3. Noutsias M, Seeberg B, Schultheiss H-P, et al. • Placebo controlled double blind study of 28 patients with Expression of cell adhesion molecules in dilated idiopathic dilated cardiomyopathy. Treatment with cardiomyopathy. Evidence for endothelial activation in pentoxifylline, an inhibitor of TNFα production, was

inflammatory cardiomyopathy. Circulation 1999;99:2124–31. associated with improvement in functional class, ejection Heart: first published as 10.1136/heart.84.1.106 on 1 July 2000. Downloaded from • The identification of immune activation in patients with IDC fraction, and a reduction in TNFα concentrations. is likely to be of increasing importance in the diagnosis of disease in patients and their relatives. In particular it may 13. Deswal A, Bozkurt B, Seta Y, et al. Safety and efficacy help to identify patients who might benefit from of a soluble P75 tumor necrosis factor receptor (Enbrel, immunomodulatory treatments. etanercept) in patients with advanced heart failure. Circulation 1999;99:3224–6. 4. European Society of . The treatment of heart • Etanercept is a soluble P75 TNFα receptor fusion protein 112 failure. The task force of the working group on heart failure that binds to and inactivates circulating TNFα. In this study of the European Society of Cardiology. Eur Heart J a single intravenous infusion resulted in improvement of 1997;18:736–53. six minute walk, ejection fraction, and quality of life score • General review and guidelines for the management of for two weeks. Etanercept is now being studied in large congestive cardiac failure. These guidelines do not take scale multicentre studies. into account recent data on β blockers, AII receptor antagonists, and spironolactone. 14. Dovai H, Nul D, Grancelli H, et al. Gruppo de Estudio de la Sobrevida en la Insuficiencia en Argentina (GESICA). 5. Packer M, Poole-Wilson P, Armstrong P, et al. The Randomised trial of low-dose amiodarone in severe ATLAS study group 1. Comparative effects of low and high congestive heart failure. Lancet 1994;344:493–8. doses of the angiotensin-converting enzyme inhibitor, • In this study, 516 patients with congestive cardiac failure lisinopril, on morbidity and mortality in chronic heart failure. were randomised to either placebo or amiodarone 300 mg Circulation 1999;100:2312. daily. Amiodarone was associated with a 28% reduction in • This paper shows that high dose ACE inhibitor treatment is relative risk. Only 12 patients had to discontinue the drug superior to low dose with regard to hospitalisation rates for because of side effects. heart failure. The study did not evaluate moderate doses, but the paper provides clear evidence that it is desirable to 15. Massie BM, Fisher SG, Radford M, et al. Effect of aim as close as possible to maximum recommended amiodarone on clinical status and left ventricular function in doses of ACE inhibitors in heart failure patients. patients with congestive heart failure. CHF-STAT 6. Pitt B, Segal R, Martinez F, Meurers G, et al. Investigators. Circulation 1996;93:2128–34. Randomised trial of losartan versus captopril in patients over • In this study, 674 patients with class II–IV heart failure 65 with heart failure (evaluation of losartan in the elderly were randomised in a double blind fashion to either study, ELITE). Lancet 1997;349:747–52. amiodarone or placebo. Amiodarone was associated with • First large study to demonstrate that angiotensin II an improvement in ejection fraction, and a significant antagonists are tolerated at least as well as ACE inhibitors. reduction in the composite end point of hospitalisation and The trial also suggested that mortality was lower in the cardiac death in patients with non-ischaemic heart failure. losartan group, but the trial was not powered to make this Compared to GESICA, many more patients in this study observation. were withdrawn from treatment because of side effects. The difference in outcome may be explained by many 7. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of factors including inclusion criteria, sex differences, candesartan, enalapril and their combination in congestive prevalence of non-sustained ventricular tachycardia, and cardiac failure. Randomized evaluation of strategies for left the aetiology and severity of heart failure. ventricular dysfunction (RESOLVD) pilot study. The RESOLVD pilot study investigators. Circulation 16. Torp-Pedersen C, Moller M, Bloch-Thomsen P, et al. 1999;100:1056–64. The Danish investigations of arrhythmia and mortality on • This study suggests that the combination of an ACE dofetilide study group. Dofetilide in patients with congestive inhibitor and an AII receptor antagonist may be more heart failure and left ventricular dysfunction. N Engl J Med effective than either agent alone in reducing neurohumoral 1999;341:857–65. activation and in preventing ventricular remodelling. Large • This study demonstrates that dofetilide, a novel class III scale trials are now underway to investigate this antiarrhythmic drug, is effective in reducing the incidence hypothesis. of atrial in patients with congestive cardiac failure. The drug is limited by the requirement for 8. Packer M, Bristow MR, Cohn JN, et al. The effect of in-hospital initiation of treatment in order to monitor for QT

carvedilol on morbidity and mortality in patients with chronic prolongation and ventricular http://heart.bmj.com/ heart failure. US carvedilol heart failure study group. N Engl tachycardia. J Med 1996;334:1349–55. • Although this study was in fact a composite of four smaller 17. McCarthy JF, McCarthy PM, Starling RC, et al. Partial studies, the results of carvedilol treatment were impressive left ventriculectomy and repair for end-stage with a dramatic 65% reduction in mortality risk and a 38% congestive cardiac failure. Eur J Cardiothorac Surg reduction in the risk of death or hospitalisation. Similar 1998;13:337–43. reductions in mortality have now been observed with • In this study 57 patients, 95% of whom had IDC and were metoprolol and bisoprolol. listed for transplantation, underwent partial left 9. CIBIS-II Investigators. The cardiac insufficiency ventriculectomy, together with mitral valve repair in 55 bisoprolol study II (CIBIS-II): a randomised trial. Lancet patients. Seventeen patients required left ventricular assist 1999;353:9–13. device rescue and only 50% were free from death or transplantation at one year. Seven patients died late after

• This study enrolled 2647 patients with stable class III/IV on September 29, 2021 by guest. Protected copyright. symptoms and ejection fraction less than 0.35. Bisoprolol surgery. treatment (target dose 10 mg) was associated with a 18. Rose EA, et al. The REMATCH trial: rationale, design, mortality rate of 11.8% compared to 17.3% in the placebo and end-points. Ann Thorac Surg 1999;67:723–30. arm. • This paper outlines the rationale behind the REMATCH 10. MERIT-HF Investigators. Effect of metoprolol CR/XL in study. In particular it discusses the difficulties in adapting chronic heart failure: metoprolol CR/XL randomised the now commonplace clinical trial model used in heart intervention trial in congestive heart failure (MERIT-HF). failure trials to the evaluation of surgical treatments. Lancet 1999;353:2001–7. 19. Auricchio A, Stellbrink C, Block M, et al for the • This study enrolled 3911 patients with stable class II–IV Pacing Therapies for Congestive Heart Failure Study Group. symptoms and ejection fraction less than 0.40. Mortality in The guidant heart failure research group. Effect of pacing the 1990 patients that received metoprolol CR/XL (target chamber and atrioventricular delay on acute systolic function dose 200 mg) was 7.2% compared to 11% (p = 0.00009). of paced patients with congestive heart failure. Circulation 11. Pitt B, Zannad F, Remme WJ, et al. The effect of 1999;99:2993–3001. spironolactone on morbidity and mortality in patients with • Study demonstrating the beneficial effects of biventricular severe heart failure. Randomized aldactone evaluation study pacing in patients with heart failure. The major predictor of investigators. N Engl J Med 1999;341:709–17. success is QRS duration. • First large scale study to show that aldosterone 20. McNamara D, Rosenblum W, Janosko K, et al. website antagonism in patients with class III/IV symptoms already Intravenous immune globulin in the therapy of myocarditis extra taking ACE inhibitors is associated with a substantial and acute cardiomyopathy. Circulation 1997;95:2476–8. reduction in mortality. The benefit occurred with low dose • In this study, high dose immunoglobulin was given to 10 treatment, without a high incidence of hyperkalaemia. Additional references adults hospitalised with class III/IV heart failure. Of the 12. Sliwa K, Skudicky, Candy G, et al. Randomised nine patients that left hospital there was an improvement appear on the investigation of effects of pentoxifylline on left ventricular in functional class and ejection fraction. This was not a Heart website performance in idiopathic cardiomyopathy. Lancet randomised trial and requires evaluation in a large scale 1998;351:1091–3. randomised study. www.heartjnl.com