Cardiomyopathy - clinical review

Section 1: Epidemiology and aetiology

Cardiomyopathy is defined 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: hypertrophic, dilated, arrhythmogenic, restrictive and unclassified. It is a significant cause of sudden death in the young.

Improvements in genetic testing have improved diagnostic accuracy and prognostication. This has reinforced the importance of genetic counselling and screening. There has been a call for modification of the current 'simplistic' classification.

Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is inherited (mostly autosomal dominant).

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 one in 5002 and it tends to affect men and black people more often. The obstructive form is seen in 25% of cases.

Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterised by an LV ejection fraction (LVEF) <45% (normally 55-70%) with increased (dilated) LV dimension. The condition is hereditary in 30-40% of cases (usually autosomal dominant), although it can be caused by acute viral (usually entero/ adenoviruses) myocarditis.

ARVC
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 genetic cause (familial in 30-50%, usually with autosomal dominant inheritance).

Although ARVC is uncommon (one in 5,000), it has regional clustering in northern Italy and Greece.^1,3

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

Loeffler 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.

Unclassified cardiomyopathy
Unclassified cardiomyopathy includes LV 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 mainly affects women and is due to catecholamine surges from physical or emotional stress, causing coronary vasospasm and severe apical, mid-LV dysfunction.

Section 2: Making the diagnosis

It is important that cardiac symptoms in the young are not underestimated. Sudden death could be the first manifestation of HCM, usually secondary to VF.

Patients may present with dyspnoea due to diastolic dysfunction, chest pain from raised oxygen demand 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 on exertion or arrhythmia, and heart failure from diastolic dysfunction or mitral regurgitation.

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 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.

Loeffler endocarditis presents acutely with fever, cough, rash, weight loss and heart failure.

Endomyocardial fibrosis has chronic symptoms and signs of congestive cardiac failure. A third heart sound (S3), reflecting impaired diastole and murmurs of tricuspid and mitral regurgitation, may be audible.

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

ARVC generally presents in men aged 15-35 with palpitations, presyncope or syncope. Sudden death could be the first presentation. Patients who survive into their fourth and fifth decades can present with biventricular or right heart failure (without pulmonary hypertension).

Takotsubo cardiomyopathy is usually precipitated by stress and presents with symptoms of acute coronary syndrome.

LVNC can manifest from the neonatal period to old age with symptoms and signs of heart failure.

Section 3: Managing the condition

Investigating cardiomyopathy in primary care is difficult but ECG, transthoracic echocardiography (TTE), Holter monitoring and blood tests such as B-type natriuretic peptide (BNP), may be available.

The first step includes a morphological diagnosis, followed by screening of first-degree relatives using a comprehensive history, ECG and echocardiography.

This is followed by genetic testing, metabolic screen, additional imaging and if required, myocardial biopsy.

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

Blood tests in DCM show elevated BNP. Other blood tests include Hb, renal function, LFTs and TFTs.

ECG may show AF and poor R-wave progression from V1 to V6. Chest X-ray may show cardiomegaly or pulmonary oedema.

Rule out an ischaemic cause for LV dysfunction using coronary angiography or non-invasive tests such as stress echocardiography, radionucleotide imaging or MRI.

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

Endomyocardial biopsy is diagnostic in secondary RCM, whereas in idiopathic cases it shows patchy fibrosis. MRI can 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. RV angiography has been considered the gold standard for diagnosis, but MRI has better sensitivity and specificity.

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 sensitivity and specificity.

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

Treatment
The objectives 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 significantly 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.

Patients with multiple risk factors for sudden death (see below) benefit from implantable cardioverter defibrillator (ICD) implantation for primary prevention.

In 2011, the American College of Cardiology/American Heart Association published a statement differing from European Society of Cardiology (ECS) guidelines by recommending ICD implantation even with a single risk factor such as severe LV hypertrophy, unexplained syncope or family history of sudden cardiac death.⁴

Recent guidelines have downgraded risk factors such as non-sustained VT and abnormal BP response on exercise in isolation.⁴

DCM is managed using drugs, cardiac resynchronisation and cardiac transplantation in patients with drug-refractory terminal heart failure. LV assist devices can also be considered.

Standard heart failure therapy does not influence prognosis in RCM. Small starting doses of ACE inhibitors and diuretics are used to reduce filling pressures, without significantly reducing cardiac output. Anticoagulation is mandatory to avoid thromboembolism.

In early phases of Loeffler endocarditis, steroids, interferon or cytotoxic drugs may improve prognosis.

Management of secondary RCM is tailored to the causative condition. 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 ICD is mandated in high-risk patients.

LV function in Takotsubo syndrome usually normalises within days or weeks. If so, medication can be stopped in three to six months.

Section 4: Prognosis

Patients with a diagnosis of HCM require risk stratification using annual exercise testing and Holter monitoring.

The patient's family members should also be screened.

Advise the patient to refrain from intense physical exertion.

Indicators of a high risk of 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="">3cm and abnormal BP response on exercise testing. Annual mortality rates have been reported to be 3-6%.

Five-year survival for patients with DCM is about 30%. Mitral regurgitation or diastolic dysfunction portend poor prognosis.

The prognosis in RCM depends on the aetiology, but is generally poor.

The prognosis is usually good in Takotsubo cardiomyopathy beyond the initial in-hospital period, but a 5% recurrence rate is reported.

Primary care has an important role in the management of patients with cardiomyopathy.

Section 5: Case study

A 57-year-old woman presented to A&E with a history of VF arrest while undergoing tooth extraction.

The paramedics restored cardiac output and on arrival, the patient was intubated and breathing spontaneously. Her BP was 110/60mmHg.

Her pulse was 108bpm regular and cardiorespiratory examination revealed the presence of S3 and fine basal crepitations. ECG showed anterolateral ST depression.

Emergency coronary angiography revealed no occlusive lesions but left ventriculography showed antero-apical akinesia with severe impairment. The patient was started on diuretics, beta-blockers, ACE inhibitors and an aldosterone antagonist.

She regained consciousness after 48 hours and was discharged on heart failure treatment after 15 days, with a diagnosis of Takotsubo cardiomyopathy.

Echocardiography showed persistent antero-apical LV hypokinesia but improved function. She was asymptomatic on review in the outpatient clinic after two months and her echocardiography showed no regional wall abnormalities and normal function.

Section 6: Evidence base

Clinical trials

The multicentre US sudden cardiac death in heart failure trial (SCD-HEFT) recruited 2,521 patients (1,210 with DCM) with LVEF ≤35% and NYHA class II or III heart failure.

Patients in the study were randomly assigned to ICD, amiodarone or placebo. ICD led to a 23% reduction in all-cause mortality and an absolute decrease in mortality of 7.2% (p = 0.007).⁵

A meta-analysis of five trials (1,854 patients with non-ischaemic cardiomyopathy) suggested ICD reduces all-cause mortality compared to medical therapy (RR reduction 31%, absolute risk reduction 2% per year).⁶

By Dr Rajiv Sankaranarayanan, cardiology specialty registrar in electrophysiology and British Heart Foundation research fellow, University of Manchester

Guidelines

• Gersh BJ, Maron BJ, Bonow RO et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124(24): 2761-96.

• NICE. Non-surgical reduction of myocardial septum. IPG040. London, NICE, February 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.

Key text

Camm AJ, Luscher TF, Serruys PW. The ESC Textbook of Cardiovascular Medicine (second edition). Oxford, Oxford University Press, 2009.

Online

• Cardiomyopathy Association www.cardiomyopathy.org/
• Cardiac Risk in the Young http://www.c-r-y.org.uk/

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References

1. Elliott P, Andersson B, Arbustini E et al. Eur Heart J 2008; 29: 270-6.

2. Maron BJ, McKenna WJ, Danielson GK et al. J Am Coll Cardiol 2003; 42: 1687-713.

3. Nava A, Bauce B, Basso C et al.

J Am Coll Cardiol 2000; 36: 2226-33.

4. Gersh BJ, Maron BJ, Bonow RO et al. Circulation 2011; 124(24): 2761-96.

5. Bardy GH, Lee KL, Mark DB et al. HAT Investigators. N Engl J Med 2008; 358(17): 1793-804.

6. Desai AS, Fang JC, Maisel WH et al. JAMA 2004; 292: 2874-9.