Cardiomyopathy/Arrhythmia | Rare Disease

Cardiomyopathy and arrhythmia: A genetic link may be at the heart of these conditions

Discover the genetic link to cardiovascular diseases like cardiomyopathy and arrhythmia and how genetic testing can help develop a care plan

Cardiomyopathy and arrhythmia are cardiovascular diseases that directly impact heart health. Each condition has multiple forms, affecting the heart differently and having varying underlying causes. Cardiopathies generally make it more difficult for the heart to pump blood throughout the body. Arrhythmias are irregular heartbeats, either too fast or too slow, which can cause blood pressure and circulation problems.

While these and other cardiovascular conditions may be associated with poor diet, lack of exercise, and risky lifestyle behaviors, like substance misuse,¹ cardiomyopathy and arrhythmia can be passed down through families.

Read on to learn about cardiomyopathies and arrhythmias and how genetic testing may help identify the heart of the problem.

How common are cardiomyopathies and arrhythmias?

According to the Centers for Disease Control and Prevention, cardiovascular diseases are the leading cause of death in men and women in the United States. Cardiomyopathies and arrhythmias are types of cardiovascular disease that impact how the heart works within the body to pump and circulate blood.

Cardiomyopathies and arrhythmias have a causal relationship, meaning one condition can cause the other in certain situations. For example, if the heart is having difficulty pumping blood throughout the body (cardiomyopathy), it may cause a disturbance in the heart rhythm (arrhythmia). Alternatively, arrhythmia-induced cardiomyopathy can also occur, resulting in heart failure.

Cardiomyopathy may be present in an estimated 1 in 500 adults. However, this condition is often undiagnosed, so the exact numbers may vary. Additionally, cardiomyopathy can impact men and women of all ages and races.²

Arrhythmias are more common than cardiomyopathy and are estimated to exist in 1.5% to 5% of individuals. Like cardiomyopathy, the exact numbers for arrhythmia prevalence may vary because some people may not show outward symptoms, and their condition can go undiagnosed.³

Are cardiomyopathies and arrhythmias inherited conditions?

While cardiomyopathy, arrhythmia and other cardiovascular diseases can have numerous causes, some types are inherited genetic conditions.

More than 1 in 150 people have an inherited form of cardiovascular disease, including genetic arrhythmias and cardiomyopathies.⁴ ⁵ This means that individuals with close family members diagnosed with cardiomyopathy or arrhythmia may be at an increased risk for developing those conditions.

One of the most common types of cardiomyopathy is an inherited form known as hypertrophic cardiomyopathy. This condition causes the heart muscle to thicken, making it more difficult for the heart to pump blood throughout the body. In some instances, hypertrophic cardiomyopathy can lead to an arrhythmia.

Other hereditary forms of cardiomyopathy include⁶-¹²:

• Dilated — thinning and weakening in one heart chamber, resulting in the inefficient pumping of blood
• Restrictive — stiffening of the heart, resulting in blood backing up in the chambers and lungs
• Left ventricle non-compaction — lower left heart chamber is underdeveloped, leading to an impaired ability to pump blood
• Arrhythmogenic right ventricular cardiomyopathy — the breakdown of the heart wall over time, resulting in arrhythmia and sudden death
• Amyloid — excess protein builds in the heart and overtakes the muscle causing heart failure
• Infiltrative — a build-up of abnormal substances in the heart leading to heart failure

Arrhythmias can also be inherited. While it’s not uncommon for irregular heartbeats to occur in people, especially during physical exertion or increased pain, prolonged arrhythmias can negatively affect the heart. Genetic arrhythmias can impact people of all races, genders and ethnicities.

The most common type of arrhythmia is atrial fibrillation, or AFib, which affects over 3 million people in the United States.¹³ AFib affects the right and left top chambers of the heart (atria), in which the chambers tremble and don’t contract correctly, which can lead to a possible blood clot or embolism.

Other types of hereditary arrhythmias include¹⁴:

• Brugada syndrome — a type of disruption in the electrical activity of the heart that can lead to cardiac arrest, especially during sleep or rest
• Catecholaminergic polymorphic ventricular tachycardia — fainting during exercise or acute emotions
• Long QT syndrome — a type of disruption in the electrical activity of the heart that can lead to cardiac arrest
• Short QT syndrome — a type of disruption in the electrical activity of the heart that can lead to cardiac arrest
• Timothy syndrome — associated with long QT syndrome but includes physical characteristics, like webbed fingers/toes and distinctive facial features
• Wolff-Parkinson-White syndrome — accessory (or additional) electrical path (or conduit) in the heart leading to heart flutters, rapid heart rate or fainting
• Arrhythmogenic right ventricular dysplasia — fatty, fibrous tissue replaces the heart muscle leading to abnormal heart rhythm or cardiac arrest
• Idiopathic ventricular fibrillation — sudden cardiac arrest without a known underlying cause

While not all cardiomyopathies and arrhythmias are genetic, knowing if there’s a family history may help make better-informed decisions regarding care options.

Are children at greater risk if their parents have hereditary cardiomyopathies or arrhythmias?

Hereditary hypertrophic cardiomyopathy and most hereditary arrhythmias are autosomal dominant, which means there is a 50% chance that a child whose parent has the condition will inherit the same genetic variant.

Having a gene variant for hereditary cardiomyopathy or an arrhythmia doesn’t automatically mean the child will develop the condition. There’s an increased risk when a first-degree relative, like a parent, passes the variant to their child. However, it’s not definitive that the child will express the condition.

For first-degree relatives of individuals with hereditary cardiomyopathies or arrhythmias, the National Human Genome Research Institute recommends discussing personal and family health histories with healthcare providers to receive individualized counseling and education regarding:

• setting up a regular screening schedule
• following a healthy diet
• counseling regarding exercise
• avoiding smoking tobacco and excessive alcohol use
• specific genetic testing that can help with diagnosis and treatment

Family planning discussions for first-degree relatives or individuals with inherited genetic conditions, like hypertrophic cardiomyopathies or arrhythmias, may help determine potential next steps.

Which genes are associated with hereditary cardiomyopathies and arrhythmias?

Hereditary cardiomyopathies

The two most common genes connected to hypertrophic cardiomyopathy are MYBPC3 and MYH7. The following additional genes have also been found to have variants causing hypertrophic cardiomyopathy: MYH6, TNNT2, TPM1, MYL2, MYL3, TNNI3 and ACTC1.¹⁵

Genetic variants that can impact other forms of hereditary cardiomyopathy include⁶-¹¹:

• Dilated — More than 30 genes have been identified, the most common being the TTN gene
• Restrictive — TNNI3
• Left ventricle non-compaction — MYH7 and MYBPC3
• Arrhythmogenic right ventricle cardiomyopathy — 13 genes have been identified, the most common being in the PKP2 gene
• Amyloid — TTR
• Infiltrative — There are many forms of this cardiomyopathy, and each has its own gene(s) associated with it

Hereditary arrhythmias

AFib is the most common form of hereditary arrhythmia. The gene variants most frequently associated with AFib are in KCNQ1, KCNH2, ABCC9, LMNA, PRKAG2, RYR2 and SCN5A.¹⁶

The other genetic conditions that can cause arrhythmias have variants in the following genes¹⁷-²³:

• Brugada syndrome — SCN5A, CACNA1C, HCN4 and TRPM4
• Catecholaminergic polymorphic ventricular tachycardia — RYR2 and CASQ2
• Long QT syndrome — KCNQ1, KCNH2 and SCN5A
• Short QT syndrome — KCNH2, KCNJ2, KCNQ1 and CACNA1C
• Timothy syndrome — CACNA1C
• Wolff-Parkinson-White syndrome — PRKAG2
• Arrhythmogenic right ventricular cardiomyopathy — PKP2, RYR2, DES, DSC2, DSP, JUP, LMNA, TGFB3 and TTN
• Idiopathic ventricular fibrillation — DPP6, CALM1, IRYR2 and IRX3

Inherited factors for cardiomyopathies and arrhythmias are more common than most people think, and genetic testing can help identify a hereditary predisposition.

How can genetic testing inform cardiomyopathy and arrhythmia care?

Given the clinical overlap between the different types of cardiomyopathies and arrhythmias, comprehensive genetic testing can enable a more efficient evaluation of multiple conditions. In fact, one in nine positive patients may be missed using disease-specific panels instead of a broad panel for inherited cardiomyopathies and arrhythmias.²⁴

In individuals with clinical symptoms of cardiomyopathy and arrhythmia, genetic testing can help confirm or establish a diagnosis, clarify risks and inform management of the condition. Knowing the exact gene variant can assist in developing a tailored care plan and help healthcare providers recommend potential next steps for treatment.

Research has shown that 84% of providers have made adjustments to their patients’ care plans due to genetic testing results,²⁵ which can help inform on treatments by²⁶:

• identifying opportunities for tailored management recommendations
• identifying patients in need of more intense cardio monitoring or device treatment
• refining clinical management options to what’s most appropriate and impactful
• identifying patients at higher risk of adverse responses to therapies
• supporting coverage of therapies or prescription medications

There’s no reason to wait until symptoms develop to undergo genetic testing. It’s available to asymptomatic individuals with a family history of cardiovascular disease. Knowing if a hereditary predisposition exists can assist an individual in making lifestyle modifications early and avoiding activities and certain types of medications to help mitigate the risk of triggering symptoms.

Invitae offers a comprehensive panel for cardiomyopathy and arrhythmia that simultaneously tests up to 168 genes.

To learn more about genetic testing in cardiology for inherited cardiovascular diseases like cardiomyopathies and arrhythmias, visit Invitae.

References

1. Know your risk for heart disease. Centers for Disease Control and Prevention. March 21, 2023. Accessed June 22, 2023. https://www.cdc.gov/heartdisease/risk_factors.htm.
2. Cardiomyopathy. Centers for Disease Control and Prevention. February 21, 2023. Accessed June 22, 2023. https://www.cdc.gov/heartdisease/cardiomyopathy.htm.
3. Professional CC medical. What you need to know about arrhythmias. Cleveland Clinic. Updated March 20, 2023. Accessed June 22, 2023. https://my.clevelandclinic.org/health/diseases/16749-arrhythmia.
4. McKenna WJ, Judge DP. Nat Rev Cardiol. 2021;18: 22–36.
5. Beheshti SO, et al. J Am Cardiol. 2020;75: 2553–2566.
6. Familial dilated cardiomyopathy: Medlineplus genetics. MedlinePlus. Updated April 1, 2017. Accessed June 22, 2023. https://medlineplus.gov/genetics/condition/familial-dilated-cardiomyopathy/#frequency.
7. Familial restrictive cardiomyopathy: Medlineplus genetics. MedlinePlus. Updated July 1, 2019. Accessed June 22, 2023. https://medlineplus.gov/genetics/condition/familial-restrictive-cardiomyopathy/#causes.
8. Left ventricular noncompaction: Medlineplus Genetics. MedlinePlus. Updated June 22, 2022. Accessed June 22, 2023. https://medlineplus.gov/genetics/condition/left-ventricular-noncompaction/#causes.
9. Arrhythmogenic right ventricular cardiomyopathy: Medlineplus genetics. MedlinePlus. Updated February 1, 2018. Accessed June 22, 2023. https://medlineplus.gov/genetics/condition/arrhythmogenic-right-ventricular-cardiomyopathy/#causes.
10. Alreshq R, Ruberg FL. Curr Opin Cardiol. 2021;36(3):309–317.
11. Kaviarasan V, et al. The Egyptian Heart Journal. 2022;74(1).
12. Vidula MK, et al. Heart. 2022;108:98–104.
13. Familial atrial fibrillation: Medlineplus genetics. MedlinePlus. October 1, 2017. Accessed June 22, 2023. https://medlineplus.gov/genetics/condition/familial-atrial-fibrillation/#causes.