Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging

Abstract

Purpose: HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing.

Methods: Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death.

Results: We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).

Conclusions: We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM.

Fig 1. Cardiac magnetic resonance characterization of a patient with a MYH7 variant.

Panel A. Cine images at end systole showing apical hypertrophy with apical aneurysm. Panel B. Delayed enhancement images showing extensive LGE in the distal myocardial segments including the apex.

Fig 2. Correlation between variant position and phenotype.

Panel A shows the correlation between variant position and left ventricular mass index. Variant position was associated with LVMI in MYBPC3 variants (p = 0.018). Panel B shows the lack of correlation between variant position of total late gadolinium enhancement.

Fig 3. Summary of associations between clinical outcomes and genetic diagnosis.

Note logarithmic scale.