Lamin A/C Cardiomyopathies (Cardiolaminopathies)

Patients usually present first with symptoms of heart blocks and/or atrial arrhythmias, including palpitations, syncope, or sudden cardiac death (1, 2).

Age at presentation is typically < 40 years. Heart failure manifestations (eg, exertional dyspnea, fatigue, peripheral edema) typically develop later, but timing is variable. An atrial cardiomyopathy with atrial fibrillation and/or systemic thromboembolism, including stroke, are more with common Lamin A/C cardiomyopathies than with other forms of dilated cardiomyopathy (3).

Approximately 15% of patients also have skeletal muscle symptoms (eg, weakness), which may precede cardiac manifestations (4).

• ECG

• Cardiac imaging (eg, echocardiography, cardiac MRI)

• Genetic testing

• Screening of first-degree relatives

Diagnosis is suspected in young patients with palpitations, syncope, or resuscitation from unexplained cardiac arrest, particularly if they also have early-onset conduction system disease, supraventricular or ventricular arrhythmias, skeletal muscle weakness, peripheral neuropathy, and/or a family history of arrhythmias and/or heart failure.

Patients should have ECG, ambulatory cardiac rhythm monitoring, and cardiac imaging, typically echocardiography and/or cardiac MRI. Variations in MRI phenotype may suggest specific underlying genetic mutations or provide prognostic information (1, 2, 3).

If conduction disturbances, tachyarrhythmias, and/or cardiomyopathy are detected, genetic testing is offered. The yield of genetic testing rises from 5% to 10% in the general population of patients with idiopathic dilated cardiomyopathy to approximately one-third in patients with AV conduction disturbances and a family history of cardiomyopathy (4, 5).

First-degree relatives of patients have a significant risk of disease. Thus, they should have clinical evaluation (ie, to detect symptoms suggestive of arrhythmia, muscle weakness, and/or heart failure), ECG, ambulatory cardiac rhythm monitoring, and echocardiography initially and then every 1 to 2 years (6). Genetic testing is performed if a causative mutation is identified in the patient. Family members who are not carriers of that mutation do not require ongoing testing.

• Moderation of physical activity

• Usually an implantable cardioverter-defibrillator (ICD)

• Sometimes antiarrhythmic medication therapy

• Low threshold for anticoagulation in patients with atrial fibrillation

• Heart failure therapy (including transplantation) as required

Treatment focuses on prevention of sudden death and prevention of symptomatic ventricular tachyarrhythmias.

Strenuous exercise, including participation in competitive sports, may hasten the progression of the cardiomyopathy and increase the risk of life-threatening arrhythmias and sudden death (1, 2). Discussion of exercise participation and restriction is individualized and may be informed by a high-risk LMNA mutation, the presence or severity of dilated cardiomyopathy, and the patient's arrhythmia history.

The 5-year risk of a first episode of life-threatening arrhythmia ranges from approximately 4% to 70% depending on sex, non-missense LMNA mutation, AV block (first-degree or higher degrees), nonsustained ventricular tachycardia, and left ventricular ejection fraction (3). An online risk calculator for patients who have not yet had a life-threatening arrhythmia is available (lmna-risk-vta.fr).

Because of a high risk of sudden death, an ICD is typically implanted earlier in the course of illness in patients with lamin A/C cardiomyopathies than in other patients with dilated cardiomyopathy, and an ICD should be considered when there are other indications for an implantable pacemaker or cardiac resynchronization therapy (4) (see table Indications for an ICD). Established indications for ICD use include patients with:

• Sustained ventricular tachycardia or ventricular fibrillation or resuscitated cardiac arrest

• Dilated cardiomyopathy plus left ventricular ejection fraction of < 35%

Placement of an ICD is reasonable for patients with lamin A/C cardiomyopathy who have (4):

• Unexplained syncope

• An independent indication for a permanent pacemaker or cardiac resynchronization therapy

• ≥ 2 other risk factors for sudden death (intermediate left ventricular ejection fraction in the range of 35% to 44%, male sex, nonsustained ventricular tachycardia)

A beta-blocker should be used in most patients but may increase the possibility of AV block. Beta-blockers should be used with caution in patients with second- or third-degree AV block without pacemaker backup.

Antiarrhythmic pharmacotherapy with a class III medication , particularly sotalol or amiodarone, may reduce symptomatic ventricular tachyarrhythmias but is not a substitute for an ICD. However, these medications may benefit patients who have frequent appropriate ICD discharges despite adequate beta-blocker therapy.

Patients with lamin A/C cardiomyopathy have an increased risk of thromboembolic complications, independent of the presence of dilated cardiomyopathy or atrial arrhythmias (5); therefore, a lower threshold for anticoagulation for atrial fibrillation is appropriate.

Standard measures for treatment of dilated cardiomyopathy are used as required.

• Lamin A/C cardiomyopathies are genetic disorders that cause tachyarrhythmias, heart block, and heart failure.

• Some of the mutations also affect skeletal muscle.

• Diagnosis is based on clinical and electrocardiographic factors, cardiac imaging, and genetic testing.

• First-degree relatives have a significant risk of disease and require screening.

• Treatment requires usually requires exercise restriction, an implantable cardioverter-defibrillator, and a beta-blocker.