What is the genetic basis of heart failure?

From the Guidelines

Heart failure has a significant genetic basis, with genetic factors contributing to approximately 30-40% of cases, and genetic testing is recommended for patients with suspected genetic heart failure, particularly those with early-onset disease, family history, or specific cardiomyopathy phenotypes. The genetic basis of heart failure is complex, involving mutations in genes encoding sarcomeric proteins, ion channels, and structural proteins, and is often characterized by autosomal dominant inheritance patterns 1. Familial cardiomyopathies, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies, are examples of genetic heart failure, and genetic testing can help identify at-risk family members and guide patient management 1.

Key Points

• Genetic factors contribute to approximately 30-40% of heart failure cases
• Familial cardiomyopathies, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies, often have clear genetic causes with autosomal dominant inheritance patterns
• Genetic testing is recommended for patients with suspected genetic heart failure, particularly those with early-onset disease, family history, or specific cardiomyopathy phenotypes
• First-degree relatives of affected individuals should undergo clinical screening with echocardiography and electrocardiography
• Treatment follows standard heart failure guidelines, but may be tailored based on specific genetic variants, such as early ICD implantation for patients with LMNA mutations due to high arrhythmia risk 1

Genetic Testing and Counseling

Genetic testing is essential for identifying at-risk family members and guiding patient management, and should ideally be initiated on the person in a family with the most definitive diagnosis and most severe manifestations 1. Genetic counseling is also crucial for affected families to understand inheritance patterns, reproductive options, and implications for relatives. The identification of a molecular cause may lead to critical gene-specific cardiac or extracardiac management recommendations, and genetic testing has been shown to be cost-effective in identifying asymptomatic affected family members and presymptomatic carriers of pathogenic variants 1.

Clinical Implications

The genetic basis of heart failure explains why some patients develop the condition despite minimal risk factors and why treatment responses vary significantly between individuals with seemingly similar clinical presentations. By understanding the genetic basis of heart failure, clinicians can provide personalized care and improve patient outcomes, and genetic testing and counseling can help identify at-risk family members and guide patient management 1.

From the Research

Genetic Basis of Heart Failure

The genetic basis of heart failure is complex and involves multiple genetic variants and mutations.

• Heart failure can be caused by Mendelian inherited forms of myocardial disease, as well as common sporadic forms of heart failure 2.
• The genetic background of heart failure is characterized by a complex architecture, with both rare and common variants contributing to the disease 3, 4.
• Genetic testing is available for several phenotypes of heart failure, including cardiomyopathies such as dilated or hypertrophic cardiomyopathy, and can aid in diagnosis and identification of at-risk family members 3, 4.

Genetic Variants and Mutations

• Nearly 100 disease-associated genes have been identified for cardiomyopathies, and the knowledge of a pathogenic mutation can be used for genetic counseling, risk and prognosis determination, and therapy guidance 4.
• The I/D polymorphism of the Angiotensin Converting Enzyme gene has been shown to influence the development of left ventricular hypertrophy, a major determinant of heart failure 5.
• Modifier genes, such as the I/D polymorphism, can play a role in the expression of the disease, and susceptibility genes have been searched for in sporadic forms of dilated cardiomyopathy 5.

Personalized Medicine

• Personalized medicine, which uses the patient's genomic information to improve diagnosis, prevention, and therapy, is a promising approach for the management of heart failure 6.
• Monogenic disorders causing heart failure, such as cardiomyopathies, can be managed using molecular diagnostics, genetic counseling, and therapeutic choices 6.
• Pharmacogenomics of heart failure appears very promising, with common genetic variants of beta-adrenergic receptors, alpha-adrenergic receptors, and endothelin receptors altering the response to heart failure therapy 6.