Prognostic Significance of β-Myosin Heavy Chain Mutations is Reflective of Their Hypertrophic Expressivity in Patients with Hypertrophic Cardiomyopathy

Abstract

Background

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 β-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 β-MyHC mutations associated with high, moderate, and low incidence of SCD.

Methods

Mutations were identified by chemical cleav-age (Val⁶⁰⁶Met and Glu⁹³⁰Lys) or polymerase chain reac-tion (PCR) and Mspl restriction mapping (Arg⁷¹⁹Gln). Left ventricular mass was determined using 2-D echocardio-grams, 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.

Results

The Arg⁷¹⁹Trp, Glu⁹³⁰Lys, and Val⁶⁰⁶Met muta-tions were associated with high (14/29, 48%), moderate (3/16, 19%), and low (1/11, 9%) risk of premature death, respec-tively. 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 muta-tions (20.7 ± 6.8 mm vs 16.2 ± 2.6 mm, p = 0.077).

Conclusion

Hypertrophic cardiomyopathy patients with the malignant Arg⁷¹⁹Trp mutation have more extensive hypertrophy than those with the benign Leu⁶⁰⁶Val mutation. This finding suggests that the prognostic significance of β-MyHC mutations is reflective of their hypertrophic expres-sivity.