Genetics of Cardiomyopathy: Clinical and Mechanistic Implications for Heart Failure

Abstract

Genetics has played an important role in the understanding of different cardiomyopathies, and the field of heart failure (HF) genetics is progressing rapidly. Much research has also focused on distinguishing markers of risk in patients with cardiomyopathy using genetic testing. While these efforts currently remain incomplete, new genomic technologies and analytical strategies provide promising opportunities to further explore the genetic architecture of cardiomyopathies, afford insight into the early manifestations of cardiomyopathy, and help define the molecular pathophysiological basis for cardiac remodeling. Cardiovascular physicians should be fully aware of the utility and potential pitfalls of incorporating genetic test results into pre-emptive treatment strategies for patients in the preliminary stages of HF. Future work will need to be directed towards elucidating the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship. This future research should aim to further our ability to identify, diagnose, and treat disorders that cause HF and sudden cardiac death in young patients, as well as prioritize improving our ability to stratify the risk for these patients prior to the onset of the more severe consequences of their disease.

Keywords: Cardiomyopathy; Dilated cardiomyopathy; Genetics; Heart failure; Hypertrophic cardiomyopathy.

Figure 1. Main structural elements of the cardiac sarcomere and their respective genes involved in the pathogenesis of hypertrophic cardiomyopathy. A schematic of definitive (bold) hypertrophic cardiomyopathy genes in sarcomere.

ACTC1 = cardiac α-actin 1; MYBPC = myosin binding protein C; MYH6 = α-myosin heavy chain; MYH7 = β-myosin heavy chain; MYL= myosin light chain; TNNI = cardiac troponin I; TNNT = cardiac troponin T; TPM1 = α-tropomyosin; TTN = titin.

Figure 2. Restrictive phenotype of the hypertrophic cardiomyopathy family.

During family screening for hypertrophic cardiomyopathy, we found that a 15-year-old male had restrictive physiology cardiomyopathy. The patient had no symptoms at that time, but the pro-BNP level was elevated and both atria were hugely enlarged. The gene test showed the same variant as his father, and the patient suddenly presented with dyspnea and cardiac arrest. The patient required heart transplantation. AF = atrial fibrillation; HCM = hypertrophic cardiomyopathy; TNNI = cardiac troponin I.

Figure 3. Schematic for employing hypertrophic cardiomyopathy genetic testing in the proband (index patient) and family members.

CMR = cardiovascular magnetic resonance; ECG = electrocardiogram; HCM = hypertrophic cardiomyopathy; LPV = likely pathogenic variant; LVH = left ventricular hypertrophy; LVWT = left ventricular wall thickness; PV = pathogenic variant; VUS = variant of uncertain significance; WES = whole exome sequencing; WGS = whole genome sequencing.

Figure 4. Recommended clinical screening of family members^* in HCM. The screening interval may be modified (e.g., at the onset of new symptoms or in families with a malignant clinical course or late-onset HCM). These screening intervals apply to at-risk family members when genetic testing has not been performed or is uninformative in the proband, or when it has identified a likely pathogenic or pathogenic variant in the at-risk family member.

HCM = hypertrophic cardiomyopathy; ECG = electrocardiogram; LVH = left ventricular hypertrophy. ^*Includes all asymptomatic, phenotype-negative, first-degree relatives deemed to be at risk for developing HCM based on family history or genotype status, and may sometimes include more distant relatives based on clinical judgment. ^†Severe family history of early HCM-related death, sudden cardiac death, early development of LVH, or other adverse complications.

Figure 5. A schematic of definitive (bold) and posited dilated cardiomyopathy genes with the subcellular localization of the encoded proteins. Pathogenic genes encode proteins that participate in many diverse biological processes of cardiomyocytes. TTN truncating mutations are the most frequent cause of dilated cardiomyopathy.

ACTC1 = cardiac α-actin 1; BAG3 = BAG cochaperone 3; DES = desmin; DSG2 = desmoglein-2; DSP = desmoplakin; EMD = emerin; FLNC = filamin C; LMNA = lamin A/C; MYBPC = myosin binding protein C; MYH6 = α-myosin heavy chain; MYH7 = β-myosin heavy chain; MYPN = myopalladin; PKP2 = plakophilin-2; PLN = phospholamban; RBM20 = RNA-binding protein 20; SCN5A = sodium voltage-gated channel alpha subunit 5; TMPO = trimethylphosphate; TNNT = cardiac troponin T; TPM1 = α-tropomyosin; TTN = titin.

Figure 6. Two cases of TTN-related dilated cardiomyopathy. Although cardiomyopathy patients with TTN truncating variants show severe left ventricular dysfunction at diagnosis, they tend to present with a good response to appropriate medical therapy and their cardiac function improves drastically.

EF = ejection fraction; LPV = likely pathogenic variant; LVEDD = left ventricular end diastolic dimension; LVESD = left ventricular end systolic dimension; TTN = titin.

Figure 7. Schematic for employing dilated cardiomyopathy genetic testing in the proband (index patient) and family.

CK = creatine kinase; CMR = cardiovascular magnetic resonance; DCM = dilated cardiomyopathy; ECG = electrocardiogram; ICD = implantable cardioverter defibrillator; LV = left ventricular; VUS = variant of uncertain significance.

Figure 8. The diversity of the cardiomyopathies results from genetic, allelic, epigenetic, and environmental heterogeneity, all of which contribute to the phenotype. Hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins. TTN truncating variants and LMNA variants are considered to be major factors for the development of dilated cardiomyopathy. Desmosome is major cause of arrhythmogenic cardiomyopathy. The treatment of a genetic cardiomyopathy will depend on the 1) penetrance of the pathogenic variant, 2) the phenotypic presentation, 3) the underlying molecular mechanisms leading cardiac involvement, and 4) the gene-environmental interactions determining the DCM phenotype.

LMNA = lamin A/C; TTN = titin.

Figure 9. Gene-environmental interaction in dilated cardiomyopathies. DCM is a complex multi-factorial disease related to genetic determinants interfering with environmental factors.

DCM = dilated cardiomyopathy; LMNA = lamin A/C; MYH7 = β-myosin heavy chain; PLN = phospholamban; RBM20 = RNA-binding protein 20; TTN = titin.