Myocardial diseases: cardiomyopathies

At a glance

1. A cardiomyopathy is a disease of the heart muscle that is not explained by coronary disease, hypertension, valve disease or congenital heart disease. Cardiomyopathies are named by the shape of the ventricle, then by their cause.
2. The five phenotypes are hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive. Many are inherited, usually as autosomal dominant traits, and others are acquired from alcohol, drugs, inflammation, infiltration, pregnancy or stress.
3. Echocardiography, ECG and cardiac MRI define the phenotype, and genetic testing often finds the cause. First-degree relatives are offered screening, because the disease may be silent until a sudden death.
4. Hypertrophic cardiomyopathy may obstruct the outflow tract; it is treated with beta-blockers, verapamil, cardiac myosin inhibitors and septal reduction. Dilated cardiomyopathy is treated as heart failure.
5. Sudden cardiac death is the main danger in the young, and an implantable defibrillator is offered to those at highest risk.

01Definition and overview

A cardiomyopathy is a disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valve disease or congenital heart disease enough to explain it. European guidance classifies cardiomyopathies first by their phenotype, what the ventricle looks like, and then by their cause, genetic or acquired:

The same gene can cause different phenotypes, and one phenotype can have many causes. Left ventricular non-compaction, a ventricle with deep trabeculations, is now regarded as a trait that can accompany any of these, not a separate cardiomyopathy. Acquired forms such as peripartum, tachycardia-induced and alcoholic cardiomyopathy are described with the phenotype they produce. Takotsubo syndrome, which is transient, is no longer classed as a cardiomyopathy by European guidance, but it is described here because it mimics one. Left-dominant arrhythmogenic disease without dilatation is now classed as NDLVC, so ARVC refers to the right ventricle by definition.

02Etiology and pathophysiology

Hypertrophic cardiomyopathy

In about 4 in 10 patients with HCM a variant in a gene for the sarcomere is found, inherited as an autosomal dominant trait with variable penetrance. The commonest are in MYBPC3 (myosin-binding protein C) and MYH7 (β-myosin heavy chain). Many of the rest have no single-gene cause, with several genes and risk factors such as hypertension and obesity contributing.

The faulty sarcomere contracts too strongly and uses too much energy. The myocytes hypertrophy and lie in disarray, and fibrosis and small-vessel disease follow. The consequences:

• Left ventricular outflow tract obstruction, in about two thirds of patients at rest or on provocation: the thick septum narrows the outflow tract, and the fast flow drags the anterior mitral leaflet towards the septum in systole (systolic anterior motion), which also causes mitral regurgitation. The obstruction is dynamic. It worsens when the ventricle is smaller or more vigorous: on standing, during Valsalva, with dehydration, vasodilators and exertion.
• Diastolic dysfunction: the thick, stiff ventricle relaxes poorly, raising the filling pressure.
• Myocardial ischaemia without coronary disease, from the mass of muscle and abnormal small vessels.
• Arrhythmias: atrial fibrillation, poorly tolerated, and ventricular arrhythmias from the disarray and scar.

Phenocopies look like HCM but have another cause, and some have specific treatments: cardiac amyloidosis, Fabry disease, Danon and Pompe disease, mitochondrial diseases, Noonan syndrome, Friedreich ataxia. The athlete's heart and hypertensive hypertrophy are the main differentials.

Dilated and non-dilated left ventricular cardiomyopathy

A genetic cause is found in about 3 in 10 patients with DCM. The commonest are truncating variants in TTN, the gene for titin, followed by LMNA (lamin A/C), DSP, FLNC, RBM20, MYH7, TNNT2 and the dystrophin gene in Duchenne and Becker muscular dystrophy. LMNA, FLNC, DSP and PLN variants cause arrhythmias and sudden death out of proportion to the ventricular dysfunction, and LMNA causes conduction disease.

Acquired causes:

• alcohol, usually more than about 80 g a day for years;
• chemotherapy: anthracyclines, dose-dependent and often only partly reversible, with the best recovery when heart failure treatment starts early, and trastuzumab, usually reversible;
• myocarditis and Chagas disease;
• persistent tachycardia, which causes a reversible dilated ventricle;
• pregnancy (peripartum cardiomyopathy);
• endocrine and nutritional causes: thyroid disease, phaeochromocytoma, thiamine and selenium deficiency;
• cocaine and amphetamines, iron overload.

Many patients have a genetic predisposition and an acquired trigger together. The ventricle dilates and contracts weakly, the stroke volume falls and the neurohormonal responses of heart failure follow. Functional mitral regurgitation, atrial fibrillation, thrombus in the ventricle and ventricular arrhythmias complicate it.

Arrhythmogenic right ventricular cardiomyopathy

ARVC is caused mostly by variants in the genes for the desmosome, the junction that holds the myocytes together, with PKP2 (plakophilin-2) the commonest, inherited as an autosomal dominant trait. Two recessive forms come with woolly hair and thick skin of the palms and soles: Naxos disease (plakoglobin) and Carvajal syndrome (desmoplakin). When the junctions fail under mechanical stress, the myocytes die and are replaced by fat and fibrous tissue, starting in the outer wall of the right ventricle. The scar causes ventricular arrhythmias early, and right or both-sided failure late. Endurance exercise speeds the process.

Restrictive cardiomyopathy

The ventricles are stiff and fill poorly, while the systolic function is near normal until late. The atria enlarge, and the filling pressures rise. Causes:

• cardiac amyloidosis, the commonest, which infiltrates and thickens the walls (and so often looks like HCM): transthyretin amyloid, either wild-type, mostly in older men, or hereditary, and light chain (AL) amyloid from a plasma cell disorder;
• sarcoidosis, haemochromatosis, Fabry disease and storage diseases;
• endomyocardial fibrosis in the tropics and Löffler endocarditis with hypereosinophilia;
• radiation and anthracyclines;
• idiopathic and familial forms, often from sarcomere variants.

Acquired cardiomyopathies and takotsubo syndrome

• Takotsubo syndrome (stress cardiomyopathy): an emotional or physical stress, or none, is followed by transient dysfunction of the left ventricle, typically ballooning of the apex with a hypercontracting base. A surge of catecholamines, coronary vasospasm and microvascular dysfunction are thought to be the cause.
• Peripartum cardiomyopathy: heart failure with an ejection fraction below 45 per cent towards the end of pregnancy or in the months after delivery, with no other cause. A fragment of prolactin that damages the endothelium, produced under oxidative stress, is thought to play a part, along with pre-eclampsia and genetic variants (often TTN).
• Tachycardia-induced cardiomyopathy: weeks of fast atrial fibrillation, flutter or frequent ectopic beats.

03Clinical features

Hypertrophic cardiomyopathy

Many patients have no symptoms and are found by family screening or an abnormal ECG. Symptoms:

• breathlessness, from diastolic dysfunction, obstruction and mitral regurgitation;
• chest pain on exertion;
• palpitations and atrial fibrillation, which can cause sudden pulmonary oedema;
• dizziness and syncope, especially during or just after exercise;
• sudden cardiac death, sometimes the first manifestation, mostly in adolescents and young adults.

The signs, in obstructive HCM: a jerky carotid pulse, a double apical impulse (a palpable atrial contraction), a fourth heart sound, and an ejection systolic murmur at the left sternal edge that is louder on standing and during Valsalva and softer on squatting, often with a pansystolic murmur of mitral regurgitation. Without obstruction, the examination may be normal.

Dilated cardiomyopathy

DCM presents with heart failure, arrhythmias (atrial fibrillation, ventricular tachycardia), conduction disease, embolism or sudden death, or is found during family screening. The signs are those of heart failure with a displaced apex, a third heart sound and the murmur of functional mitral regurgitation. Muscle weakness, a raised creatine kinase or conduction disease points to a lamin or dystrophin gene.

Arrhythmogenic right ventricular cardiomyopathy

Young adults, often athletes, present with palpitations, syncope or sudden death during exertion, from ventricular tachycardia with a left bundle branch block shape, starting in the right ventricle. Right heart failure appears late.

Restrictive cardiomyopathy and amyloidosis

Patients have right-sided congestion out of proportion to the size of the heart: a raised JVP that rises on inspiration, hepatomegaly, ascites and oedema, with breathlessness, fatigue and atrial fibrillation. Cardiac amyloidosis has its own clues: thick walls with a low-voltage ECG, intolerance of blood pressure drugs, bilateral carpal tunnel syndrome, lumbar canal stenosis and rupture of the biceps tendon (transthyretin), or macroglossia, periorbital bruising and proteinuria (light chain). A peripheral or autonomic neuropathy points to light chain or hereditary transthyretin amyloid.

Takotsubo and peripartum cardiomyopathy

Takotsubo syndrome presents like an acute myocardial infarction: chest pain and breathlessness, ST elevation or T wave inversion and a raised troponin, mostly in postmenopausal women. Peripartum cardiomyopathy presents with breathlessness, orthopnoea and oedema around delivery, symptoms easily put down to pregnancy itself.

04Diagnosis and management

The approach to every cardiomyopathy

• A three-generation family history, asking about sudden deaths, heart failure, pacemakers and neuromuscular disease.
• ECG: in HCM, left ventricular hypertrophy, deep T wave inversion and pathological Q waves; in ARVC, T wave inversion in V1 to V3 and epsilon waves; in amyloidosis, low voltage and a pseudo-infarct pattern; in LMNA disease, atrioventricular block.
• Echocardiography: the wall thickness and its distribution, the cavity size, systolic and diastolic function, the outflow gradient at rest and with Valsalva or exercise, and the valves.
• Cardiac MRI, recommended in every patient: precise measurement, scarring (late gadolinium enhancement) and its pattern, which points to the cause (patchy mid-wall in HCM and DCM, diffuse subendocardial in amyloidosis, right ventricular in ARVC).
• Holter monitoring for arrhythmias, an exercise test, natriuretic peptides, and blood tests for acquired causes (thyroid function, iron studies, creatine kinase, serum and urine tests for a monoclonal protein).
• Coronary angiography or CT to exclude coronary disease in DCM.
• Genetic testing in the patient, with counselling, and then cascade testing of relatives for the family variant. Relatives who do not carry it can be discharged; carriers and relatives of patients without a known variant have regular clinical screening.

Hypertrophic cardiomyopathy

Obstruction means a peak gradient of 30 mmHg or more, and 50 mmHg or more is the threshold for invasive treatment. For symptomatic obstruction:

• beta-blockers, titrated to the highest tolerated dose, first;
• verapamil or diltiazem if beta-blockers fail or are not tolerated;
• a cardiac myosin inhibitor (mavacamten, or aficamten), added when symptoms persist, or alone when the other drugs cannot be used. It reduces the excess contractility at its source: in a randomised trial mavacamten lowered the gradient and improved symptoms and exercise capacity. It is started only with an ejection fraction of 55 per cent or more and paused if it falls below 50 per cent, and drug interactions (and, for mavacamten, the CYP2C19 genotype) set the dose;
• disopyramide as an added drug;
• septal reduction, by surgical myectomy or alcohol septal ablation, in patients with a gradient of 50 mmHg or more and severe symptoms despite drugs, in experienced centres.

Vasodilators (nitrates, dihydropyridines, phosphodiesterase inhibitors), high-dose diuretics, digoxin and dehydration worsen obstruction and are avoided. Non-obstructive HCM with symptoms is treated with beta-blockers or verapamil, and with heart failure treatment if the ventricle fails late in the disease.

Every patient with HCM and atrial fibrillation is anticoagulated, whatever the stroke score, because the risk of stroke is high.

Prevention of sudden death:

• an implantable defibrillator for survivors of cardiac arrest or sustained ventricular tachycardia;
• for primary prevention, a validated score estimates the 5-year risk from age, maximal wall thickness, left atrial size, the outflow gradient, a family history of sudden death, non-sustained ventricular tachycardia and unexplained syncope. A defibrillator should be considered when the risk is 6 per cent or more and may be considered between 4 and 6 per cent, or lower when there is extensive scar on MRI (15 per cent or more of the ventricle) or an ejection fraction below 50 per cent. American guidance also counts an apical aneurysm.

Exercise of low and moderate intensity is encouraged in everyone. More intense exercise and competitive sport may be possible for selected patients without risk markers, after specialist assessment.

Dilated cardiomyopathy

DCM is treated as heart failure with reduced ejection fraction, with the full range of heart failure drugs, and with cardiac resynchronisation for a wide QRS. Causes are removed where possible: abstinence from alcohol, control of a tachycardia, a change of chemotherapy. Anticoagulation is given for atrial fibrillation or thrombus in the ventricle.

The decision about a defibrillator for primary prevention is more selective than in ischaemic heart disease, because a large trial showed that a defibrillator in non-ischaemic heart failure halved sudden deaths but did not lower overall mortality. It is weighed with the ejection fraction (35 per cent or less after at least three months of treatment), scarring on MRI, syncope and the genotype, and offered earlier with LMNA, FLNC, DSP, PLN and RBM20 variants. Advanced disease needs a ventricular assist device or transplantation.

Arrhythmogenic right ventricular cardiomyopathy

The diagnosis uses criteria that combine structure, tissue, ECG, arrhythmias and family history and genetics. Treatment:

• no competitive or high-intensity sport for patients; healthy gene carriers are usually advised to avoid it too, on weaker evidence;
• beta-blockers;
• antiarrhythmic drugs (amiodarone, sotalol, flecainide with a beta-blocker) and catheter ablation for ventricular tachycardia;
• a defibrillator after cardiac arrest or sustained ventricular tachycardia, and for primary prevention by risk score;
• heart failure treatment and, rarely, transplantation.

Restrictive cardiomyopathy and amyloidosis

Restriction must be told apart from constrictive pericarditis, which surgery cures. Treatment is of congestion with diuretics, of atrial fibrillation with anticoagulation, and of the cause.

In suspected amyloidosis:

• tests for a monoclonal protein (serum free light chains, and immunofixation of serum and urine) come first, because AL amyloidosis is a haematological emergency that needs chemotherapy;
• if there is no monoclonal protein, bone scintigraphy with strong cardiac uptake diagnoses transthyretin amyloid without a biopsy, and genetic testing separates the hereditary form from the wild-type form;
• transthyretin amyloid is treated with stabilisers of transthyretin (tafamidis, acoramidis) or drugs that silence its production (vutrisiran), which reduce deaths and admissions; AL amyloid with chemotherapy based on daratumumab;
• the patients tolerate beta-blockers and ACE inhibitors poorly, because their small, stiff ventricles depend on heart rate and filling, so diuretics are the mainstay for symptoms.

Takotsubo syndrome

Coronary angiography is needed to exclude an infarction. Treatment is supportive. Shock from outflow tract obstruction is treated with fluids and beta-blockers, and catecholamine inotropes are avoided, because they may worsen the condition; levosimendan or mechanical support are alternatives. Thrombus in the ballooned apex needs anticoagulation.

Peripartum cardiomyopathy

It is treated as heart failure, adapted to pregnancy. Before delivery, ACE inhibitors, ARNI, mineralocorticoid antagonists and SGLT2 inhibitors are avoided because they harm the fetus or have not been shown to be safe in pregnancy, while beta-blockers, diuretics and hydralazine with nitrates can be used; after delivery the usual treatment follows, with drugs chosen to be safe in breastfeeding. Bromocriptine, which blocks prolactin, may be added after delivery, with anticoagulation. A further pregnancy carries a risk of relapse and death, high if the ventricle has not recovered, so patients need advice before conceiving.

05Epidemiology

HCM affects about 1 in 500 adults, which makes it the commonest inherited heart disease; many carriers are never diagnosed. DCM affects between 1 in 2500 and 1 in 250 adults, and it is the commonest reason for heart transplantation. ARVC affects about 1 in 1000 to 1 in 5000 people, and it is a leading cause of sudden death in young athletes in some regions, such as northern Italy. Restrictive cardiomyopathy is rare, but transthyretin amyloid is increasingly recognised in older men with heart failure and preserved ejection fraction. About 9 in 10 patients with takotsubo syndrome are women, mostly after the menopause, and it accounts for about 2 per cent of suspected acute coronary syndromes. Peripartum cardiomyopathy affects about 1 in 1000 to 1 in 4000 deliveries in Europe and the US, more in Africa and Haiti.

06Prognosis

Most patients with HCM have a near-normal life expectancy. The yearly risk of sudden death in adults is under 1 per cent, higher in the young and in those with risk markers, and the main causes of illness are heart failure, atrial fibrillation and stroke. A minority progress to a dilated, poorly contracting "burnt-out" phase.

The outlook in DCM has improved with modern heart failure treatment, and many patients recover some ventricular function; truncating TTN variants often respond well, while LMNA variants carry a high risk of arrhythmia and heart failure. ARVC progresses, with the risk of arrhythmia highest in young, active patients, but a defibrillator gives most a good survival. Untreated cardiac amyloidosis has a poor prognosis, worst in AL amyloid, though modern drugs have improved both forms.

In takotsubo syndrome the ventricle usually recovers within weeks, but the acute phase is not benign: in-hospital death occurs in about 4 per cent, similar to an acute coronary syndrome, and the syndrome recurs in about 2 per cent of patients a year. About half of women with peripartum cardiomyopathy recover a normal ejection fraction within 6 months; others are left with chronic heart failure.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1A 19-year-old footballer has an ejection systolic murmur at the left sternal edge that gets louder when he stands up and during a Valsalva manoeuvre, and softer when he squats. What is the most likely cause?

Aortic stenosisAn innocent flow murmurHypertrophic cardiomyopathy with outflow tract obstructionA ventricular septal defect

2Which drug should be avoided in a patient with obstructive hypertrophic cardiomyopathy?

A nitrate such as glyceryl trinitrateBisoprololVerapamilMavacamten

3A 78-year-old man has heart failure, thick ventricular walls on echocardiography, a low-voltage ECG and a past history of carpal tunnel syndrome in both wrists. Which tests can diagnose transthyretin amyloid cardiomyopathy without a biopsy?

Coronary angiography and an exercise testBone scintigraphy showing cardiac uptake, with serum and urine tests showing no monoclonal proteinA genetic test for MYH7A raised troponin and BNP

4A 22-year-old cyclist has palpitations. He has runs of ventricular tachycardia with a left bundle branch block shape, T wave inversion in V1 to V3 and a dilated right ventricle with scarring on MRI. What should he be advised about sport?

He can continue training if he takes a beta-blockerSport is safe once the palpitations stopNo restriction is neededHe should stop competitive and high-intensity sport

5A 68-year-old woman develops chest pain the day after her husband's funeral. Her ECG shows ST elevation, her troponin is raised and her coronary arteries are normal. The left ventricular apex balloons while the base contracts strongly. What is the diagnosis?

Takotsubo syndromeMyocarditisArrhythmogenic cardiomyopathyHypertrophic cardiomyopathy