Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline
Section snippets
The Family as the Unit of Care
A critical transition for cardiovascular practitioners who wish to more fully actualize cardiovascular genetic medicine is to adopt the family as the unit of care, a concept inherently understood by genetics professionals. For cardiovascular providers, moving the care paradigm beyond the patient (proband), who often presents with a fully developed phenotype and at times with advanced life-threatening disease, to at-risk relatives is mandatory to fulfill the promises of precision medicine.
Types of Cardiomyopathy
The genetic basis of hypertrophic cardiomyopathy (HCM) is well established as largely a disease caused by mutations in genes encoding sarcomeric proteins. That familial dilated cardiomyopathy (DCM) has a genetic basis is also well accepted. (The term DCM is used herein instead of the more technical attribution “idiopathic dilated cardiomyopathy,” where the other common and easily clinically detected causes of systolic dysfunction such as coronary artery disease, primary valvular or congenital
Approaches to Review and Publication by the ACMG and HFSA
The writing group was established conjointly with the ACMG and HFSA from 2013 to 2015. The approaches to creating, curating, and approving practice guidelines or practice resources for the HFSA and ACMG, respectively, have been outlined in each group's publication. The material covered in this and the companion document24 are congruent with one another. Differences in scope, including supplemental materials, are denoted and cross-referenced.
The writing group was composed of a panel of
Use of Medical Evidence in This Guideline
We address 2 questions here. The 1st question is that of clinical validity: “Does the evaluation or test correlate with the outcome of interest?”25 Because randomized clinical trials evaluating the clinical accuracy of diagnosis with or without a genetic evaluation or genetic testing are not generally feasible, as in the previous guideline1 we have used a different format for level of evidence. By genetic evaluation we mean a systematic approach that includes a comprehensive family history,
Guideline 1
Obtaining a family history of at least 3 generations, including the creation of a pedigree, is recommended for all patients with a primary cardiomyopathy.Cardiomyopathy Phenotype Level of Evidence Hypertrophic cardiomyopathy (HCM) A Dilated cardiomyopathy (DCM) A Arrhythmogenic right ventricular cardiomyopathy (ARVC) A Restrictive cardiomyopathy (RCM) A Cardiomyopathies with extracardiac manifestations A Left ventricular noncompaction (LVNC) See Background
Guideline 2
Clinical (phenotypic) screening for cardiomyopathy in at-risk 1st-degree relatives is recommended.Cardiomyopathy Phenotype Level of Evidence Hypertrophic cardiomyopathy (HCM) A Dilated cardiomyopathy (DCM) A Arrhythmogenic right ventricular cardiomyopathy (ARVC) A Restrictive cardiomyopathy (RCM) A Cardiomyopathies, overlapping, or extracardiac A Left ventricular noncompaction (LVNC) See Background
Guideline 3
Referral of patients with genetic, familial, or other unexplained forms of cardiomyopathy to expert centers is recommended.
- 3a.
Infants and children with cardiomyopathy should be evaluated by clinicians with specific expertise in the recognition and testing of syndromic and nonsyndromic presentations of cardiomyopathy in this age group.
Guideline 4
Genetic testing is recommended for patients with cardiomyopathy.
- 4a.
Genetic testing is recommended for the most clearly affected family member.
- 4b.
Cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants.
- 4c.
In addition to routine newborn screening tests, specialized evaluation of infants with cardiomyopathy is recommended, and genetic testing should be considered.
Cardiomyopathy Phenotype | Level of Evidence |
---|---|
Hypertrophic cardiomyopathy (HCM) | A |
Guideline 5
Genetic counseling is recommended for all patients with cardiomyopathy and their family members. (Level of Evidence = A)
Guideline 6
Focused cardiovascular phenotyping is recommended when pathogenic or likely pathogenic variants in cardiomyopathy genes, designated for reporting of secondary findings by the ACMG, are identified in an individual.
- 6a.
If a cardiovascular phenotype is identified as would be predicted by currently available knowledge of the gene/variant pair, all usual approaches described in this document for a genetic evaluation, including family-based approaches, are recommended.
- 6b.
If no cardiovascular disease
Therapy Based on Genetic Evaluation and Cardiac Phenotype
The clinical characteristics associated with variants in some disease genes, when integrated with pedigree data, may directly influence the overall assessment and clinical recommendations for a patient or family.
One gene with substantial evidence fitting this situation is LMNA, which commonly presents with nonsyndromic cardiomyopathy in adult cardiology practice and is well known for progressive conduction system disease (1st-, 2nd-, or 3rd-degree heart block), usually with supraventricular
Guideline 7
Medical therapy based on cardiac phenotype is recommended, as outlined in consensus guidelines. (Level of Evidence = A)
Guidelines for the evaluation and management of patients with cardiomyopathy have been published for HCM,137, 138 DCM,6, 139, 140, 141 and ARVC.142 These guidelines provide comprehensive guidance for care of those who are presymptomatic (stage B heart failure) or have had the onset of symptoms (stage C or D heart failure). Guidelines for the clinical care of patients with RCM
Guideline 8
Device therapies for arrhythmia and conduction-system disease based on cardiac phenotype are recommended, as outlined in consensus guidelines. (Level of Evidence = B)
In brief, ICDs are indicated for secondary prevention of ventricular tachycardia or ventricular fibrillation regardless of the type of cardiomyopathy or degree of ventricular dysfunction. The indications for ICDs for primary prevention of sudden cardiac death in patients with nonischemic cardiomyopathy with reduced LVEF of any
Guideline 9
In patients with cardiomyopathy and significant arrhythmia or known risk of arrhythmia, an ICD may be considered before the LVEF falls below 35%. (Level of Evidence = C)
Electrophysiologic disease can be considered broadly as conduction system disease and arrhythmia (see the discussion above regarding LMNA cardiomyopathy), but this guideline applies to any genetic cardiomyopathy that presents or progresses to lethal arrhythmia or heart block before advanced LV dysfunction. Examples of other
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