Clinical Review: Cardiomyopathy

Contributed by Dr Rajiv Sankaranarayanan, a cardiology specialty registrar in electrophysiology, Manchester Heart Centre, Manchester.

Still image of transthoracic echocardiogram in DCM showing a dilated left ventricle (Photograph: Dr Raj Thakkar)
Still image of transthoracic echocardiogram in DCM showing a dilated left ventricle (Photograph: Dr Raj Thakkar)

Section 1: Epidemiology and classification
Cardiomyopathy is defined by the European Society of Cardiology as 'a myocardial disorder in which heart muscle is structurally and functionally abnormal without coronary artery disease, hypertension, valvular or congenital heart diseases'.1

There are five types of cardiomyopathy: hypertrophic, dilated, arrhythmogenic, restrictive or unclassified. Cardiomyopathy is a significant cause of sudden death in the young. Therefore, primary care has an important role both in aiding early diagnosis as well as raising awareness of these conditions in the community.

Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is inherited. It is characterised by disorganised cardiac myocytes and unexplained left ventricular (LV) hypertrophy due to mutations in the genes encoding sarcomeric proteins, such as cardiac beta-myosin heavy chain gene, troponin and alpha-tropomyosin.

The prevalence of HCM is about 1 in 5002 and it is more common in men and black people. The obstructive form (HOCM) is seen in 25 per cent of cases.

Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterised by an LV ejection fraction <45 per="" cent="" normally="" 55-70="" with="" increased="" dilated="" lv="" dimension="" p="">

The condition is hereditary in 30-40 per cent of cases (usually autosomal dominant); however, it can be caused by acute viral (usually entero-/adenoviruses) myocarditis leading to chronic inflammation, ventricular remodelling and dysfunction.

Restrictive cardiomyopathy
Restrictive cardiomyopathy (RCM) is sub-classified into primary (Loeffler's endocarditis, endomyocardial fibrosis) and secondary (infiltrative causes: amyloidosis, sarcoidosis; storage disorders: haemochromatosis, glycogen storage disorder, Fabry's disease; post-radiation).

Loeffler's endocarditis is caused by acute eosinophilic myocarditis with mural thrombosis and fibrotic thickening at the apex of one or both ventricles. Endomyocardial fibrosis is the chronic form.

Arrhythmogenic right ventricular cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is caused by fibro-fatty replacement of right ventricular (RV) myocytes due to apoptosis, inflammation (definite causes for either mechanism are as yet unknown) or a genetic cause (familial in 30-50 per cent usually with autosomal dominant inheritance). Though ARVC is uncommon (1 in 5,000), it has regional clustering in northern Italy and Greece.1,3

Unclassified cardiomyopathy
Unclassified cardiomyopathy includes left ventricular non-compaction (LVNC) and Takotsubo cardiomyopathy.

LVNC is caused by embryogenic arrest of normal myocardial maturation causing a loose meshwork of non-compacted myocardial fibres with deep recesses communicating with the LV cavity.

Takotsubo cardiomyopathy (neurogenic myocardial stunning), predominantly affects women and is due to catecholamine surges from physical or emotional stress, causing coronary vasospasm and severe apical, mid-LV dysfunction.

Section 2: Clinical features
It is important that cardiac symptoms in young patients are not underestimated as this can lead to fatal delays in diagnosis.

HCM
Patients may present with dyspnoea due to diastolic dysfunction, chest pain and impaired diastole of hypertrophied myocardium, palpitations (ectopic beats, AF or flutter, supraventricular tachycardia or ventricular tachycardia (VT)), presyncope/syncope due to inadequate cardiac output.

Characteristic signs include double carotid impulse, prominent 'a' wave on the JVP, laterally displaced double apical impulse and fourth heart sound (S4).

The ejection systolic murmur is best heard between the apex and left sternal edge radiating to the suprasternal notch, intensifying with reduced preload (standing/Valsalva manoeuvre) or afterload (vasodilators) and diminishing with increased preload (squatting) or afterload (handgrip).

DCM
DCM presents with dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, ankle oedema and weight gain. A viral prodrome with malaise, flu-like illness or chest pain from antecedent myocarditis may be present.

Clinical signs include tachycardia, pulmonary rales and signs of right heart failure, such as peripheral oedema, ascites and raised JVP.

RCM
Loeffler's endocarditis presents acutely with fever, cough, rash, weight loss and heart failure, which could lead to death. Complications include systemic embolism, and neurological and renal dysfunction.

Endomyocardial fibrosis presents with chronic symptoms and signs of congestive cardiac failure. A third heart sound (S3), reflecting impaired diastole, and murmurs of tricuspid and mitral regurgitation are usually audible.

Secondary infiltrative conditions have peripheral stigmata (easy bruising, macroglossia, periorbital purpura in amyloidosis; skin pigmentation, arthropathy, cirrhosis in haemochromatosis; multi-organ involvement in sarcoidosis and storage disorders).

ARVC
ARVC can present in men aged 15-35 years with palpitations, presyncope or syncope due to exercise-induced VT. Death could be the first presentation when VT degenerates into VF.

Patients who survive into their fourth and fifth decades can present with biventricular or right heart failure (without pulmonary hypertension).

Unclassified
Takotsubo cardiomyopathy is usually precipitated by physical or emotional stress and presents with symptoms of acute coronary syndrome. Physical examination may reveal signs of left ventricular failure or even cardiogenic shock.

LVNC can manifest from the neonatal period to old age with symptoms and signs of heart failure and its complications, such as arrhythmias (VT in up to 40 per cent patients) and thromboembolism.

Section 3: Investigation and management
The availability of ECG, transthoracic echocardiography (TTE), Holter monitoring and blood tests in some GP surgeries has aided early diagnosis of cardiomyopathy.

However, these investigations are not always available in primary care, further underlining the importance of early referral to secondary and tertiary care.

Typical findings
ECG in HCM shows LV hypertrophy and ST-T wave abnormalities. TTE is diagnostic, showing asymmetric septal hypertrophy (usually >15 mm) with a ratio of septal wall to posterior wall thickness >1.4:1.

Blood tests in DCM show elevated brain natriuretic peptide (marker of long-term mortality and also guides treatment response). ECG may show AF and poor R-wave progression from V1 to V6.

Chest X-ray may show cardiomegaly or pulmonary oedema. It is important to rule out an ischaemic cause for LV dysfunction using coronary angiography or non-invasive tests.

In Loeffler's endocarditis, blood tests show eosinophilia and raised inflammatory markers. ECG shows non-specific ST-T changes and arrhythmias. Chest X-ray may show pulmonary congestion.


Infiltrates and RA thrombus in RCM due to cardiac lymphoma

Echocardiography shows preserved systolic function (early stages), apical thickening in primary RCM, dilated atria, mitral and tricuspid regurgitation, diastolic dysfunction and may show thrombi and infiltrates in secondary RCM.

Endomyocardial biopsy is diagnostic in secondary RCM, whereas in idiopathic cases it shows patchy fibrosis. MRI can non-invasively demonstrate infiltrative conditions or differentiate from constrictive pericarditis.

Diagnosing ARVC is difficult due to non-specific disease features and phenotypic manifestations. Echocardiographic features include increased RV dimensions, RV regional wall motion abnormalities and dysfunction.

In LVNC, echocardiography is diagnostic showing a two-layered myocardium (thicker inner layer and thin compacted outer layer). Colour Doppler also shows blood filling directly from the LV cavity into deep intertrabecular recesses. MRI has greater diagnostic sensitivity and specificity.

In Takotsubo cardiomyopathy, ECG shows ST elevation or T wave inversion. Troponin is elevated in about 90 per cent of patients. Coronary angiography shows normal coronaries but typical apical ballooning and severe LV impairment, which may also be seen on echocardiography.


Takotsubo cardiomyopathy showing apical ballooning

Treatment
GPs play an important role in reinforcing the implications of diagnosis, lifestyle changes, compliance with treatment, and follow-up and referral of family members for screening.

The objectives of treatment in HCM are to alleviate symptoms and prevent complications. Beta-blockers, verapamil and disopyramide reduce LV outflow tract gradient and diastolic dysfunction but do not suppress ventricular arrhythmias.

Amiodarone suppresses atrial and ventricular arrhythmias. Patients with drug-refractory symptoms, resting outflow gradients of 30-50mmHg or increasing to >50mmHg with exercise or isoproterenol infusion qualify for surgical myectomy (primary treatment option) or alcohol septal ablation to reduce LV outflow gradient.

Therapy
DCM is managed using drugs, cardiac resynchronisation therapy and cardiac transplantation in patients with drug-refractory terminal heart failure.

Left ventricular assist devices can also be considered a bridge to transplant or sustained recovery. Small starting doses of ACE inhibitors and diuretics are used to reduce filling pressures, without significantly reducing cardiac output. Anticoagulation is mandatory to avoid thrombo-embolism.

During early phases of Loeffler's endocarditis, steroids, interferon or cytotoxic drugs may improve prognosis. Management of secondary RCM is tailored to treatment of the causative condition.

Surgical therapy with endocardial decortication or valve replacement can be considered in treatment-refractory cases or for symptom palliation.

In ARVC, severe RV dysfunction is treated with standard heart failure medications and cardiac transplantation is considered if treatment is refractory. Beta-blockers are used in asymptomatic patients and implantable cardiovascular defibrillator (ICD) is mandated in high-risk patients (syncope, documented VT, cardiac arrest, frequent complex ventricular ectopic beats and family history of premature sudden cardiac death).

Heart failure in LVNC and Takotsubo cardiomyopathy is treated with standard therapy. LV function in Takotsubo syndrome usually normalises within days to weeks. If so, medications can be stopped within three to six months.

Section 4: Follow-up and prognosis
HCM patients need risk stratification using annual exercise testing and Holter monitoring. Family members should be screened. Advise the patient to refrain from physical exertion.

Indicators of a high risk for sudden death include age <30 years="" unexplained="" syncope="" family="" history="" of="" premature="" sudden="" cardiac="" death="" arrest="" vf="" spontaneous="" sustained="" vt="" or="" non-sustained="" on="" holter="" monitoring="" lv="" thickness="">3 cm and an abnormal BP response on exercise testing.

Five-year survival for DCM patients is about 30 per cent.

Mitral regurgitation or diastolic dysfunction portend poor prognosis. Prognosis in RCM depends on aetiology, but is generally poor.

The prognosis is good in Takotsubo cardiomyopathy beyond the initial in-hospital period but a 5 per cent recurrence rate is reported. Primary care has an important role in management of patients.

Section 5: Case study
A 38-year-old man presented with a three-month history of exertional dyspnoea associated with left-sided chest pain. He was a non-smoker with no prior medical problems. His father died suddenly of a presumed heart attack aged 40 years.

Clinical examination showed normal BP, regular pulse and a systolic murmur in the aortic area. His routine blood tests were within normal limits. He was referred to a cardiology out-patient clinic urgently for further evaluation.

Further history taking in clinic revealed three episodes of exertional syncope. Clinical examination also revealed a double apical impulse at 2cm lateral to the mid-clavicular line, S4 and an ejection systolic murmur best heard between the apex and left sternal edge and intensifying upon Valsalva manoeuvre.

Diagnosis
Transthoracic echocardiography performed in the cardiology clinic showed asymmetric septal hypertrophy (2cm) with systolic anterior motion of the mitral valve (which may reduce cardiac output), normal aortic valve function and an LV outflow gradient of 28mmHg at rest.

This gradient went up to 76mmHg on exercise treadmill testing accompanied by a BP drop of 30mmHg.

The patient was diagnosed with HOCM and started on propranolol. Seven-day Holter monitoring identified frequent episodes of non-sustained VT. Cardiac catheterisation showed normal coronary arteries.

Implantable cardioverter defibrillator
In view of the family history and non-sustained VT on Holter monitoring, he received an ICD. As he remained severely symptomatic (New York Heart Association (NYHA) Classification 3-4), he underwent successful surgical septal myectomy.

The patient remains asymptomatic and attends for annual follow-ups.

Summary and role of primary care

  • Cardiomyopathy is an important cause of sudden death in the young.
  • Diagnosis of cardiomyopathy can be challenging and family history, physical examination, as well as ECG, can be crucial.
  • Any patient with suspected cardiomyopathy should be referred to a cardiologist as both the diagnosis and management can be difficult.
  • Once the diagnosis is made, primary care plays an important role in reinforcing the need for lifestyle modifications, adherence to treatment and follow-up as well as ensuring referral of relatives for screening where appropriate.

Section 6: Evidence base
Clinical trials

Many factors predictive of sudden death in ischaemic LV dysfunction are not predictive in non-ischaemic DCM.

Early trials, such as the cardiomyopathy trial (CAT), amiodarone versus implantable cardioverter defibrillator trial (AMIOVIRT) and defibrillators in non-ischaemic cardiomyopathy treatment evaluation (DEFINITE) did not demonstrate significant survival benefit from ICD in DCM.

DEFINITE did show that ICD reduced sudden arrhythmic death due to low event rate and small sample size. The landmark multi-centre American trial on sudden cardiac death in heart failure (SCD-HEFT) recruited 2,521 patients (1,210 DCM patients) with LVEF ≤35 per cent and NYHA Class 2 or 3 heart failure.

The patients were randomly assigned to ICD, amiodarone or placebo. ICD therapy led to a 23 per cent reduction in all-cause mortality and an absolute decrease in mortality of 7.2 per cent (p=0.007).4

Subgroup analysis showed a similar survival benefit in ischaemic (HR 0.79, p=0.05) and non-ischaemic patients (HR 0.73, p=0.06).

A meta-analysis of five trials (1,854 patients with non-ischaemic cardiomyopathy) suggested that ICD therapy reduces all-cause mortality compared with medical therapy (relative risk reduction - 31 per cent, absolute risk reduction 2 per cent per year).5

As yet there have been no large-scale randomised trials comparing alcohol septal ablation with surgical myectomy for symptom relief in drug-refractory patients with HOCM.

The American College of Cardiology and the European Society of Cardiology (ACC/ESC) guidelines recommend surgical myectomy as the primary treatment option, and alcohol ablation in patients with high surgical risks.2

Guidelines

  • NICE. Non-surgical reduction of myocardial septum. IPG040. London, NICE, 2004.
  • Elliott P, Andersson B, Arbustini E et al. Classification of the cardiomyopathies: a position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29: 270-6.
  • Maron BJ, McKenna WJ, Danielson GK, et al. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 42: 1687-713.

Key texts

  • Camm AJ, Luscher TF, Serruys PW. ESC Textbook of Cardiovascular Medicine, 2nd edition. European Society of Cardiology, Oxford University Press, Oxford, 2009. Chapter 18 - Myocardial Disease.
  • Braunwald LP. Heart Disease. A textbook of cardiovascular medicine. Philadelphia, Saunders/Elsevier, 2008. Part VII. Disease of the Heart, Pericardium, and Pulmonary Vascular BedCardiomyopathies.

Curriculum
The RCGP covers this topic in statement 15.1 Cardiovascular problems.

Online

References
1. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29: 270-6.

2. Maron BJ, McKenna WJ, Danielson GK, et al. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 42: 1687-713.

3. Nava A, Bauce B, Basso C, et al. Clinical profile and long-term follow-up of 37 families with ARVC. J Am Coll Cardiol 2000; 36: 2226-33.

4. Bardy GH, Lee KL, Mark DB, et al. HAT Investigators. Home use of automated external defibrillators for sudden cardiac arrest. N Engl J Med 2008; 358(17): 1793-804.

5. Desai AS, Fang JC, Maisel WH, Baughman KL. Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. JAMA 2004; 292: 2874-9.

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