Genetic Insight Into the Underpinnings of Heart Failure

Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and/or rhythmogenesis cardiomyopathy (ACM) are three of the more common myopathies that lead to heart failure . HCM, thickening of the ventricular wall, and DCM, dilation of the ventricle, are more prevalent in the population than ACM. ACM is associated with loss of cardiac myocytes and fatty infiltration leading to heart failure and sudden cardiac death . Individuals with familial HCM, DCM, or ACM may demonstrate a classical Mendelian or near Mendelian inheritance pattern . In some cases, a mutation in more than one gene exists. In other cases, the myopathy may arise from hypertension, the environment, diet, or additional factors. Table 10.1 provides a list of genes with supportive evidence associating it with HCM, DCM, and/or ACM. This table also provides a short note on the function of the gene. For example, it has been estimated that 80% of all inherited HCM’s result from mutations in genes that encode proteins that comprise the contractile thick filaments MYH7 and comb-C. These proteins are involved in contraction and force generation (see Fig. 10.1 ). A mutation of cMyBP-C results in a decrease or absence of the cMyBP-C protein due to premature stop codons or frame shift mutations. Mice heterozygous for cMyBP-C exhibit increased hypertrophy and decreased ejection fraction compared to controls in response to transverse aortic constriction, suggesting that the genetic mutations in cMYBP-C leading to loss of this protein result in hypertrophy . In some cases, the details as to how the mutation alters the function of the gene/protein are not yet understood. Mutations in MYH7 , which encodes beta-myosin heavy chain, the protein responsible for generating force in the cardiac myocyte, fall into this category . Mutations in MYH7 have been associated with HCM as well as DCM , yet the mechanism(s) as to how the specific mutations lead to HCM or DCM have not been elucidated. Of note, an important finding was published in 2016, identifying methodological shortcomings that have contributed to errors in the medical literature—specifically the misclassification of benign variants as pathogenic due to the inadequate number of ancestry-matched controls . It is expected that variants will be reclassified with time as the number of individuals from different ancestries are sequenced.

Schematic diagram of the thick and thin filaments in the cardiac myocyte.

Adopted from Coppini R., Ho C.Y., Ashley E., Day S., Ferrantini C., Girolami F., et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014;64:2589–2600.

A landmark paper, published in 2012, showed that Titin truncating mutations are a common cause of DCM, occurring in 25% of familial cases of idiopathic DCM and 18% of sporadic DCM . Titin is known as the largest sarcomeric protein within the heart. Titin is alternatively spliced in the heart and thus expresses as two major isoforms, N2B and N2BA. These isoforms are incorporated into the Z-line, the I-band, the A-band, and the M-line . Mutations in the Titin gene have also been associated with arrhythmogenic right ventricular cardiomyopathy . In more recent work, we have learned that Titin missense variants are very common and are frequently benign . Truncating Titin mutations appear to be rare in HCM . A study from the European INHERITANCE project including 639 patients with sporadic or proven familial DCM was investigated at eight different clinical centers across Europe . Specifically, a standardized protocol was applied for next generation sequencing of 84 genes. When the investigators included predicted disease variants, the genes with the highest number of mutations included titin , plakophilin-2, myosin-binding protein-C-3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A . Greater than 38% of patients had more than one mutation, and 12% of patients carried more than two mutations .

The more recent finding of mutations in bcl-2 -associated athanogene 3 ( BAG3 ) associating with familial DCM highlight an example of how genetics identifies pathways associated with heart failure. BAG3 is a chaperone damage-sensing protein. Bag3-deficient mice develop cardiomyopathy with markers of degeneration of myofibrils and apoptosis . These findings suggest that BAG3 is critical for maintenance of the myocyte or microenvironment in response to the constant stresses. If this pathway is damaged, the heart is at risk of failure. In sum, genetic findings such as BAG3 that underlie DCM may lead to new diagnostic tools or therapies for heart failure.

Recent evidence using whole exome sequencing in two multigenerational Italian families and one United States family suggests that two novel splicing variants in filamin C have been associated with arrhythmogenic DCM in distinct families .