Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM), or clinically unexplained hypertrophy of the heart, is a common genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. As the genetic mutations underlying the pathogenesis of this disease have been identified, investigators have attempted to link mutations to clearly defined alterations in survival in hopes of identifying prognostically relevant biomarkers of disease. While initial studies labeling particular MYH7-encoded beta myosin heavy chain and TNNT2-encoded cardiac troponin T mutations as “malignant” or “benign” raised hopes for mutation-specific risk stratification in HCM, a series of subsequent investigations identified mutations in families with contradictory disease phenotypes. Furthermore, subsequent proband-based cohort studies indicated that the clinical prognostic relevance of individual mutations labeled as “malignant” or “benign” in large referral centers is negligible. Herein, we seek to summarize the controversy and dispute the notion that mutation-specific risk stratification in HCM is possible at the present time. We provide evidence for clinicians and basic scientists alike to move beyond simple mutation descriptors to a more nuanced understanding of HCM mutations that fully captures the multi-factorial nature of HCM disease expression.

Figure 1:

Pie chart of the proportion of our 1064-proband HCM cohort that hosted literature-described “malignant” and “benign” mutations. Clinical characteristics of these patients, such as whether the proband underwent myectomy, are noted. FH, family history; SCD, sudden cardiac death; ICD, implantable cardioverter-defibrillator.

Figure 2:

Drawing of the proteins which comprise the cardiac myofilaments include MYPBC3-encoded myosin binding protein C and MYH7 encoded β-myosin heavy chain. Clinical characteristics for patients hosting MYBPC3 and MYH7 mutations are given and adapted from Van Driest et al. Drawing adapted from Spirito et al. Dx, age at diagnosis in years; LVWT, left ventricular wall thickness; FH, family history; SCD, sudden cardiac death.

Figure 3:

A) Top, table of the associations between clinical characteristics and a positive and negative HCM genetic test. Variance measured as standard deviation. Dx, diagnosis; MLVWT, maximal left ventricular wall thickness; FH, family history; ICD, implantable cardioverter-defibrillator. Bottom, table of the hazard ratio and 95% confidence interval of a positive HCM genetic test compared with age, left ventricular outflow tract obstruction, and atrial fibrillation. Adapted from Van Driest et al. B) Kaplan-Meier analysis of the probability of cardiovascular (CV) death, nonfatal ischemic stroke, or progression to heart failure with a negative and positive HCM genetic test.