A diagnosis of dilated cardiomyopathy was made by the presence of both (1) an ejection fraction <0.45 by echocardiographic or radionuclide examination, and/or an M-mode echo fractional shortening less than 30%, and (2) a left ventricular end diastolic dimension (LVEDD) > 2.7 cm/m2, excluding any known cause of myocardial disease (20). These criteria, including the echocardiographically derived upper limits of normal LVEDD of 2.7 cm/m2, were derived from a NHLBI sponsored workshop (30). Eighty family members were identified in 1987, and 13 were considered to be affected. Linkage was established for chromosome 9q13-q22 with a maximum multipoint lod score of 4.2, with the locus placed between D9S153 and D9S152 (20). Of note, the investigators observed complete concordance of genetic linkage data when retrospectively compared to data from subjects with a normal ejection fraction but enlarged left ventricular end-diastolic dimensions by echocardiography.

Olson and Keating, 1996; chromosome 3(p22-p25). The second pedigree with arrhythmia as the presenting feature was from Utah in February, 1996 (22). The pedigree was a Utah family previously described by Anderson and coworkers (35) and included 103 members of five generations with sinoatrial dysfunction, sinus bradycardia and intermittent sinus node arrest, followed by atrial fibrillation, flutter and occasionally atrial tachycardias, and then in later years variably by atrial and possibly ventricular enlargement (35). Olson and Keating developed a point scoring system to classify 35 family members (0 points - unaffected, 1-4 points, uncertain, >4 affected) with scoring for arrhythmias (sinus bradycardia or sinus node dysfunction, incomplete or complete bundle branch block, supraventricular tachycardia, first degree AV block, complete bundle branch block < 30 yrs), clinical heart failure, atrial or ventricular dilatation, or stroke < age 40 (22). Ventricular dysfunction was defined as a echocardiographic fractional shortening < 28-30%, which approximates an ejection fraction less than 50-55%. Ventricular dimensions were not provided. Linkage was established to D3S2303 with a 2 point lod score of 6.09, and was mapped to a 30 cM region of chromosome 3p22-p25 (22

Olson and Keating, 1996; chromosome 3(p22-p25). The second pedigree with arrhythmia as the presenting feature was from Utah in February, 1996 (22). The pedigree was a Utah family previously described by Anderson and coworkers (35) and included 103 members of five generations with sinoatrial dysfunction, sinus bradycardia and intermittent sinus node arrest, followed by atrial fibrillation, flutter and occasionally atrial tachycardias, and then in later years variably by atrial and possibly ventricular enlargement (35). Olson and Keating developed a point scoring system to classify 35 family members (0 points - unaffected, 1-4 points, uncertain, >4 affected) with scoring for arrhythmias (sinus bradycardia or sinus node dysfunction, incomplete or complete bundle branch block, supraventricular tachycardia, first degree AV block, complete bundle branch block < 30 yrs), clinical heart failure, atrial or ventricular dilatation, or stroke < age 40 (22). Ventricular

Ventricular dysfunction was defined as a echocardiographic fractional shortening < 28-30%, which approximates an ejection fraction less than 50-55%. Ventricular dimensions were not provided. Linkage was established to D3S2303 with a 2 point lod score of 6.09, and was mapped to a 30 cM region of chromosome 3p22-p25 (22).

Fatkin, et al, 1999; lamin A/C; chromosome 1(q21.2-q21.3). Fatkin, MacRae and Sasaki (who all contributed equally this report) from the Seidman laboratory in Boston (29), described five FDC families with mutations in the LMNA gene, herein termed the lamin A/C gene, which is located on chromosome 1q21.2 to 1q21.3. The lamin A/C gene encodes 4 isoforms by alternative splicing of its 12 exons; exons 1-10 are common to both. Lamins A and C are components of the nuclear membrane located in the lamina, a structure associated with the nucleoplasmic surface of the inner nuclear membrane. Mutations in these proteins have been associated with an autosomal dominant form of Emery-Dreifuss muscular dystrophy (MD). The mechanism of skeletal muscle dysfunction, like the cardiomyopathy, is unknown. Emery-Dreifuss MD, most commonly an X-linked disease caused by mutations in emerin, another protein component of the nuclear envelope, is an uncommon type of MD that is manifested by progressive wasting and weakness of muscles in a humeroperoneal distribution in childhood, and commonly progresses to heart block in adulthood (although cardiac contractile dysfunction is very uncommon).

In this report five of eleven families with FDC and conduction system disease were observed to each have a missense mutations of the lamin A/C gene; none of these mutations were found in 150 chromosomes from normal subjects. Four of these mutations were observed in the rod portion of lamin common to both A and C; the fifth was observed in the tail portion of lamin C (Family A).

The onset of clinically apparent cardiovascular disease in 39 subjects from the five FDC families was in early middle age (mean 38 years, range 19-53), usually with asymptomatic electrocardiographic abnormalities of rate and rhythm; most progressed to sinus node or AV node dysfunction, or first, second or third degree heart block; over one-half had atrial fibrillation or flutter, and over one-half had pacemakers. Of note, two-thirds also had dilated cardiomyopathy, from mild LV dysfunction (12 subjects) to heart failure (13 subjects); six subjects required cardiac transplantation; eleven subjects died suddenly. Cardiac manifestations, and their severity, varied between the five families as well as within families. No evidence of muscular dystrophy was observed; creatine kinase levels were normal except for members of family A, the only family with a mutation in the carboxyl tail of lamin C; interestingly this family also had a milder cardiac phenotype (29).

The mechanism for conduction system disease from these lamin A/C mutations is not yet understood (29).

F. Clinical Recommendations for Familial Dilated Cardiomyopathy.

Clinical recommendations have been clearly outlined in our recent report (1). Those recommendations have been detailed elsewhere in this section (go to Clinical Recommendations) and will not be further reviewed here. Each of the clinical reports reviewed above in Section B also have clinical recommendations woven into the discussion in general congruent to those we have provided here.

References.

large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol, 1999;

2. Hershberger RE, Ni H, and Crispell KA. Familial dilated cardiomyopathy: echocardiographic diagnostic criteria for classification of family members as affected. J Cardiac Failure, 1999;51:203-212.

3. Battersby E and Glenner G. Familial cardiomyopathy. Am 1. Crispell K, Wray A, Ni H, Nauman D, and Hershberger R. Clinical profiles of four J Med, 1961;30:382-391.

4. Emanuel R. Familial cardiomyopathies. Postgrad Med J, 1972;48:742-745.

5. Fuster B, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, and Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol, 1981;47:525-531.

6. Johnson RA and Palacios I. Dilated cardiomyopathies of the adult. N Engl J Med, 1982;307:1051-1058.

7. Fragola PV, Autore C, Picelli A, Sommariva L, Cannata D, and Sangiorgi M. Familial idiopathic dilated cardiomyopathy. Am Heart J, 1988;115:912-914.

8. McMinn T and Ross J, Jr. Hereditary dilated cardiomyopathy. Clin Cardiol, 1995;18:7-15.

9. Berko BA and Swift M. X-linked dilated cardiomyopathy. N Engl J Med, 1987;316:1186-1191.

10. Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, Marrosu MG, Cianchetti C, Realdi G, Cao A, and Melis MA. Brief report: Deletion of the dystrophin muscle-promoter region associated with x-linked dilated cardiomyopathy. N Engl J Med, 1993;329:921-925.

abstract
Dilated Cardiomyopathy is an uncommon disease in children but morbidity and mortality in affected patients are high. This review discuses clinical presentation, diagnosis, medical management and prognosis of the condition, with an emphasis on recent advances that have influenced management of these children.

Article

Presentation and investigation dilated cardiomyopathy
 

Echocardiography is confirmatory showing dilatation of cardiac chambers, with or without mitral regurgitation (figure 2), and reduced ventricular function on M Mode analysis. It is very important to exclude mural thrombus on echocardiogram as its presence requires urgent treatment.
 

Figure 2a: Echocardiographic apical four chamber view

of dilated cardiomyopathy - note mitral regurgitation

Figure 2b: Echocardiographic parasternal long axis view

of dilated cardiomyopathy

Figure 2c: Echocardiographic parasternal long axis view

of dilated cardiomyopathy - note mitral regurgitation

Both coronary arteries should be identified in an attempt to exclude anomalous origin of the left coronary artery form the pulmonary artery although this can be difficult ¹ and angiography may be required (figure 3).

 Figure 3: Aortogram in anomalous origin

of left coronary artery

The electrocardiogram may be more useful in this respect showing deep Q waves in lead I and wide Q waves in lead AVL, where the origin of the left coronary artery is anomalous.²

More commonly in idiopathic DCM sinus tachycardia, increased left ventricular voltages and ischaemic changes are seen on ECG at presentation. The QRS complex may be broad due to conduction disturbance and evidence of right atrial hypertrophy and left atrial hypertrophy is sometimes evident. 24 hour ECG monitoring will exclude chronic tachycardia with secondary ventricular dilatation e.g. permanent junctional reciprocal tachycardia, which is associated with a moderate increased heart rate and an abnormal P axis and will also identify children with secondary arrhythmias.

Differential diagnosis
There are a number of alternate diagnoses that need to be excluded at the time of presentation, as management and therapeutic strategies may need to be altered accordingly. Anomalous origin of the left coronary artery, the ECG features of which are described above, usually presents at 2-3 months and can be confirmed at cardiac catheter. This condition is surgically correctable. Myocarditis is more difficult to diagnose with accuracy but an attempt should be made as spontaneous resolution is likely and short-term mechanical support may be more appropriate than referral for transplantation. Positive viral cultures or increased antibody titres on paired serum samples may help. Common causes include viral infection with coxachie, echo, HIV, measles, mumps and rubella but all families of micro-organisms have been implicated. Myocardial biopsy is rarely indicated, because of the risk.

In most children dilated cardiomyopathy is a sporadic condition of unknown cause. However familial cases have been reported with autosomal dominant with incomplete penetrance, recessive and x-linked inheritance patterns described. Michels et al³ demonstrated a prevalence of familial disease in 20% of index cases in a prospective study where asymptomatic first-degree relatives were screened. No features specific to familial disease have been identified. It is our policy to offer such screening, and this needs to be handled sensitively.

DCM as a secondary disease
DCM is rarely due to systemic disease however as myocardial damage may be reversible with treatment of the underlying pathology it is essential to attempt to rule out metabolic, endocrine, storage, mitochondrial and connective tissue disorders at first presentation. Blood may be taken for lactate, glucose, amino acids, carnitine and acylcarnitine, cholesterol and triglycerides, thyroid function, creatinine kinase, iron and iron binding capacity and uric acid. A full blood count to assess absolute neutrophil count and vacuolated lymphocytes may also be helpful. Early morning urine analysis for amino-acids, organic acids and glycosamine glycans may further exclude metabolic disease.

Medical management
The objective of drug therapy in DCM is to give supportive relief and maximize cardiac function. There is not as yet a treatment that offers a cure.

Diuretic have an established role particularly in their ability to produce rapid symptom relief, but earlier use of ACE inhibitors has probably resulted in lower doses being used in recent years. ACE inhibitors have been consistently shown to reduce morbidity and mortality in adult studies, ^4,5 Enalapril maleate was used in these series, there is limited information available on its use in children where captopril is most commonly prescribed. ACE inhibitors are generally well tolerated, their principle side effects include first dose hypotension, non-productive cough, and a risk of hyperkalaemia, especially in patients already on potassium supplements or potassium sparing diuretics.

Treatment with B-blockers needs also to be considered. The increased sympathetic drive that occurs as a compensatory mechanism in chronic heart failure appears to have an inverse relationship with prognosis ^6,7. B-blockers down regulate this sympathetic overdrive ⁸ and the evidence that they improve outcome in adult patients with chronic heart failure is increasing ^9,10,11. The a-adrenergic effects of the third generation B-blockers e.g. Carvedilol and Timolol also cause vasodilatation and this may be helpful.

Digoxin has a place as an orally active inotrope, but its failure to actively reduce mortality in adults ¹² means it is increasingly relegated to second line therapy. Intravenous inotropes may occasionally be necessary to support the child in end stage cardiac failure. Their use is an indication for transplant assessment in some centres ¹³
 
 

Prognosis
Mortality for DCM is highest in the first year after diagnosis with a reported survival at 1 and 5 years after first presentation of 79% and 61% respectively.¹⁵ Early deaths are principally caused by severe heart failure. Some late deaths are sudden, presumably due to arrhythmia, in children who fail to recover to normal ventricular function. While it is accepted that the risk of mortality is high there is less agreement as to predictors of poor outcome. Failure of improvement or deterioration in shortening fraction, ventricular arrhythmias, detection of mural thrombus, presentation at age >2years, endocardial fibroelastosis and left ventricular end diastolic pressure > 20mmHg have all been put forward as adverse prognostic factors. ^15,16,17,18

Mechanical and surgical support
 

End stage cardiac failure secondary to DCM has been the most common indication for heart transplantation in children and adolescents. ²⁰ Survival statistics post transplantation are improving. In a series reported from Great Ormond Street, Adwani reported survival for 95% at 1 year and 87% at 3 years, in patients transplanted for dilated cardiomyopathy.¹³ Currently the principle limiting factor in paediatric cardiac transplantation is a shortage of donor organs hence the importance of developing a mechanical support system suitable for use in the long term.

A second surgical option is the Batista operation where a partial left ventriculectomy is combined with mitral valve repair to restore left ventricular dimensions to normal thus improving pump function. Paediatric experience of this operation is limited but a 55% 2 year survival was reported in adult patients in the US, with most survivors showing symptomatic improvement.²¹

Conclusion
Management of children with dilated cardiomyopathy remains difficult but recent advances including early introduction of ACE inhibitors and B-blockers may improve what is currently a bleak outlook. In the future implantable left ventricular assist devices may provide interim mechanical support, but referral for transplantation remains the cornerstone of treatment.

References

1.     Robinson PJ, Sullivan ID, Kumpeng V, Anderson RH, MacCartney FJ. Anomalous origin of the left coronary artery form the pulmonary trunk: potential for false negative diagnosis with cross-sectional echocardiography. Br Heart J 1984;52:272-277

2.     Johnsrude CL, Perry JC, Cecchin F, O’Brian-Smith E, Fraley K, Friedman RA, Towbin JA. Differentiating Anomalous left main coronary artery originating form the pulmonary artery in infants from myocarditis and dilated cardiomyopathy by electrocardiogram. Am J Cardiol 1995;75:71-74

3.     Michels VV, Moll PP, Miller FA et al. The Frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992;326:77-82

4.     The SOLVED Investigators. Effects of Enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293-302

5.     The CONSENUS Trial Study Group. Effects of enalapril on mortality in severe congestive cardiac failure; results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;316:1429-1435

6.     Podrid PJ et al . Role of the sympathetic nervous system in the genesis of ventricular arrhythmias. Circ 1990;82(Suppl 1):103-113

7.     Cohn JN, LevineTB, Olivara MT, et al Plasma norepinepharine as a guide to prognosis in patients with chronic heart failure. N Engl J Med 1984;311:819-823

8.     Sackner-Bernstein JD, Mancini DM. Rational for treatment of patients with chronic heart failure with adrenergic blockade. JAMA 1995;274:1462-1467

9.     Bristow MR, Gilbert EM, Abraham WT et al. Carvedilol produces dose related improvements in left ventricular function and survival in subjects with chronic heart failure. Circ 1996;94:2807-2816

10.                        Packer M, Collucci WS, Sackner-Bernstein JD, et al. Double blind, placebo controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial: Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circ 1996;94:2793-2799

11.                        Australia/ New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of heart failure in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997;349:375-380

12.                        The Digitalis Investigation Group. The effect if digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533

13.                        Adwani SS, Whitehead BF, Rees PG, Whitmore P, J W Fabre, Elliot MJ, de Leval MR. Heart Transplantation for dilated cardiomyopathy. Arch Dis Child 1995;73:447-452

14.                        Fazio S, Domenico S, Brunells C, Vigorito C, Giordano A, Raffaele G, Pardo F, Biondi B, Sacca L. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med 1996;334:809-814

15.                        Burch M, Siddiqi S, Celermajer D, Scott C, Bull C, Deanfield J. Dilated cardiomyopathy in children: determinants of outcome. Br Heart J 1994;72:246-250.

16.                        Griffin M, Hernandez A, Martin T, Goldring D, Bolman M, Spray T, Strauss A. Dilated Cardiomyopathy in Infants and Children. J Am Coll Cardiol. 1988;11:139 –144.

17.                        Lewis A. Prognostic value of echocardiography in children with dilated cardiomyopathy. Am Heart J 1994;128:133-136.

18.                        Arola A, Tuominen J, Ruuskanen O, Jokien E. Idiopathic Cardiomyopathy in Children: Prognostic Indicators and Outcome. Paediatrics 1998;101: 360-376

19.                        Westaby S, Katsumata T, Houel R et al Jarvik 2000 Heart. Potentila for bridge to myocyte recovery. Circ 1998;98:1568-1574

20.                        Hosenpud JD, Novick RJ, Breen TJ, Keck BS, Daily P. The registry of the International Society for Heart and Lung transplantation: 12^th official report 1995. J Heart Lung Transplant. 1995;14:805-815

21.                        Fraizer OH, Benedict CR, Radovanceivc, B et al. Improved left ventricular function after chronic left ventricular off loading. Ann Thorac Surg. 1996;62:675-682

A diagnosis of dilated cardiomyopathy was made by the presence of both (1) an ejection fraction <0.45 by echocardiographic or radionuclide examination, and/or an M-mode echo fractional shortening less than 30%, and (2) a left ventricular end diastolic dimension (LVEDD) > 2.7 cm/m2, excluding any known cause of myocardial disease (20). These criteria, including the echocardiographically derived upper limits of normal LVEDD of 2.7 cm/m2, were derived from a NHLBI sponsored workshop (30). Eighty family members were identified in 1987, and 13 were considered to be affected. Linkage was established for chromosome 9q13-q22 with a maximum multipoint lod score of 4.2, with the locus placed between D9S153 and D9S152 (20). Of note, the investigators observed complete concordance of genetic linkage data when retrospectively compared to data from subjects with a normal ejection fraction but enlarged left ventricular end-diastolic dimensions by echocardiography.

Olson and Keating, 1996; chromosome 3(p22-p25). The second pedigree with arrhythmia as the presenting feature was from Utah in February, 1996 (22). The pedigree was a Utah family previously described by Anderson and coworkers (35) and included 103 members of five generations with sinoatrial dysfunction, sinus bradycardia and intermittent sinus node arrest, followed by atrial fibrillation, flutter and occasionally atrial tachycardias, and then in later years variably by atrial and possibly ventricular enlargement (35). Olson and Keating developed a point scoring system to classify 35 family members (0 points - unaffected, 1-4 points, uncertain, >4 affected) with scoring for arrhythmias (sinus bradycardia or sinus node dysfunction, incomplete or complete bundle branch block, supraventricular tachycardia, first degree AV block, complete bundle branch block < 30 yrs), clinical heart failure, atrial or ventricular dilatation, or stroke < age 40 (22). Ventricular dysfunction was defined as a echocardiographic fractional shortening < 28-30%, which approximates an ejection fraction less than 50-55%. Ventricular dimensions were not provided. Linkage was established to D3S2303 with a 2 point lod score of 6.09, and was mapped to a 30 cM region of chromosome 3p22-p25 (22

Definitions:

The Cardiomyopathies

(from the Greek: kardia, heart; mys, muscle; pathos, suffering)

Cardiomyopathies are defined by the World Health Organization as diseases of the myocardium associated with ventricular dysfunction. They are classified as dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy.

Dilated cardiomyopathy: Characterized by dilatation and impaired contractility of the left (or right) ventricle. Presentation is usually with heart failure. Arrhythmia, thromboembolism, and sudden death are common. Click here to view an example of dilated cardiomyopathy.

Hypertrophic cardiomyopathy: Characterized by left (or right) ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typically, left ventricular volume is reduced. Systolic gradients are sometimes present. Typical presentations include dyspnea, arrhythmia, and sudden death. Click here to view an example of hypertrophic cardiomyopathy.

Restrictive cardiomyopathy: Characterized by restrictive filling of the left (or right) ventricle with normal or near normal ventricular contractility and wall thickness. Presentations are usually with heart failure. Click here to view an example of restrictive cardiomyopathy.

The cardiomyopathies are not the only causes of the heart failure syndrome. In western countries, coronary artery disease with resultant ischemic cardiomyopathy remains the primary cause of the heart failure syndrome.