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

Date Published: June 14, 2019

Publisher: Public Library of Science

Author(s): Robert J. H. Miller, Shahriar Heidary, Aleksandra Pavlovic, Audrey Schlachter, Rajesh Dash, Dominik Fleischmann, Euan A. Ashley, Matthew T. Wheeler, Phillip C. Yang, Vincenzo Lionetti.

http://doi.org/10.1371/journal.pone.0217612

Abstract

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.

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.

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). 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.

Partial Text

Hypertrophic cardiomyopathy (HCM) is a common hereditary cardiac disorder with a prevalence of approximately 2 cases per 1000 persons.[1] It is caused by mutations in genes encoding sarcomere proteins, [2,3] with more than two dozen putative disease-associated genes identified. MYH7 encoding the β-myosin heavy chain and MYBPC3 encoding cardiac myosin-binding protein C are the most common genes harboring causative mutations.[4–6] HCM is a frequent cause of sudden cardiac death (SCD) in youth and a significant underlying pathology for cardiac morbidity and mortality in adults.[5] It is believed that myocardial fibrosis, a hallmark of HCM, contributes to the development of SCD, ventricular tachyarrhythmias, and congestive heart failure (CHF).[7–11]

Classically HCM has been characterized by poor correlation between genotype and phenotype. We sought to establish a correlation using CMR to characterize morphology which has potential benefits over echocardiography for this purpose. The high temporal and spatial resolution of CMR with superior intrinsic contrast allows more precise evaluation of myocardial morphology and reproducible quantitative assessment of ventricular volumes and function. [26–29] We found that patients with MYBPC3 variants were more likely to have impaired ventricular function compared to patients with MYH7 variants and had a trend towards an increase in arrhythmic events, with a higher proportion of patients receiving ICDs. Finally, we found that LGE burden was higher in patients with identifiable gene variants. Our findings, in a small population, suggest that there is correlation between genotype and phenotype, however the impact on clinical outcomes is less clear.

CMR may be useful to characterize genotype-phenotype relationships in HCM. 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.

 

Source:

http://doi.org/10.1371/journal.pone.0217612

 

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