PROGNOSTIC-SIGNIFICANCE OF BETA-MYOSIN HEAVY-CHAIN MUTATIONS IS REFLECTIVE OF THEIR HYPERTROPHIC EXPRESSIVITY IN PATIENTS WITH HYPERTROPHICCARDIOMYOPATHY

Background: Genotype-phenotype correlation studies consistently have s hown that mutations are prognosticators in patients with hypertrophic cardiomyopathy (HCM). While Arginine (Arg)(719)Tryptophan (Trp) mutati on in the beta-myosin heavy chain (MyHC) gene is associated with a hig h incidence of sudden cardiac death (SCD), the Valine (Val)(606)Methio nine (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 expressiv ity. We determined the indices of left ventricular hypertrophy (LVH) i n patients with beta-MyHC mutations associated with high, moderate, an d low incidence of SCD. Methods: Mutations were identified by chemical cleavage (Val(606)Met and Glu(930)Lys) or polymerase chain reaction ( PCR) and MspI restriction mapping (Arg(719)Gln). 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 semiquanti tative point score method that takes into account the extent of involv ement of the septum, apex, and lateral wall of the left ventricle. Res ults: The Arg(719)Trp, Glu(930)Lys, and Val(606)Met mutations were ass ociated with high (14/29, 48%), moderate (3/16, 19%), and low (1/11, 9 %) risk of premature death, respectively. Concordant with the incidenc e of premature death, the LVMI was the greatest (148.0 +/- 37 g/m(2)) in patients with the Arg(719)Trp mutation, the smallest (111.7 +/- 19 g/m(2)) in patients with the Val(606)Met mutation, and in between (127 .1 +/- 15 g/m(2)) in patients with the Glu(930)Lys mutation (p = 0.023 ). Similarly, the LVH score was also greater in patients with the Arg( 719)Trp mutation than in those with the Val(606)Met mutation (5.92 +/- 2.3 vs 3.2 +/- 1.5, respectively, p = 0.015). A trend toward a greate r septal thickness was also present in patients with the Arg(719)Trp c ompared to the Val(606)Met mutations (20.7 +/- 6.8 mm vs 16.2 +/- 2.6 mm, p = 0.077).Conclusion: Hypertrophic cardiomyopathy patients with t he malignant Arg(719)Trp mutation have more extensive hypertrophy than those with the benign Leu(606)Val mutation. This finding suggests tha t the prognostic significance of beta-MyHC mutations is reflective of their hypertrophic expressivity.