Prognostic significance of beta-myosin heavy chain mutations is reflective of their hypertrophic expressivity in patients with hypertrophic cardiomyopathy.

Genotype-phenotype correlation studies consistently have shown that mutations are prognosticators in patients with hypertrophic cardiomyopathy (HCM). While Arginine (Arg)719Tryptophan (Trp) mutation in the beta-myosin heavy chain (MyHC) gene is associated with a high incidence of sudden cardiac death (SCD), the Valine (Val)606Methionine (Met) mutation in the same gene is associated with a near normal life expectancy. It is unknown whether the prognostic significance of mutations is reflective or independent of their hypertrophic expressivity. We determined the indices of left ventricular hypertrophy (LVH) in patients with beta-MyHC mutations associated with high, moderate, and low incidence of SCD.Mutations were identified by chemical cleavage (Val606Met and Glu930Lys) or polymerase chain reaction (PCR) and MspI restriction mapping (Arg719Gln). Left ventricular mass was determined using 2-D echocardiograms, and was indexed (LVMI) for body surface area. The extent of LVH was determined using a semiquantitative point score method that takes into account the extent of involvement of the septum, apex, and lateral wall of the left ventricle.The Arg719Trp, Glu930Lys, and Val606Met mutations were associated with high (14/29, 48%), moderate (3/16, 19%), and low (1/11, 9%) risk of premature death, respectively. Concordant with the incidence of premature death, the LVMI was the greatest (148.0 +/- 37 g/m2) in patients with the Arg719Trp mutation, the smallest (111.7 +/- 19 g/m2) in patients with the Val606Met mutation, and in between (127.1 +/- 15 g/m2) in patients with the Glu930Lys mutation (p = 0.023). Similarly, the LVH score was also greater in patients with the Arg719Trp mutation than in those with the Val606Met mutation (5.92 +/- 2.3 vs 3.2 +/- 1.5, respectively, p = 0.015). A trend toward a greater septal thickness was also present in patients with the Arg719Trp compared to the Val606Met mutations (20.7 +/- 6.8 mm vs 16.2 +/- 2.6 mm, p = 0.077).Hypertrophic cardiomyopathy patients with the malignant Arg719Trp mutation have more extensive hypertrophy than those with the benign Leu606Val mutation. This findings suggests that the prognostic significance of beta-MyHC mutations is reflective of their hypertrophic expressivity.