Clinical Features and Outcomes of Pediatric MYH7-Related Dilated Cardiomyopathy

Abstract

Background: Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7-related DCM.

Methods and results: We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P=0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P=0.03) were the best predictors of bad prognosis.

Conclusions: Pediatric MYH7-related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

Keywords: MYH7; dilated cardiomyopathy; genetics; pediatric.

Figure 1. Variant location in MYH7 transcript.

The figure displays the location of variants included in this cohort, its domains within myosin (S1, S2, LMM) and its subdomains (ATPBS, ActinBS and Ring 1). S1: globular head (amino acids 1–847); S2: neck region (amino acids 848–1216); light meromyosin (amino acids 1217–1936); ATP‐binding site (amino acids 130–260); actin‐binding site (amino acids 385–515 and 577–611); Ring 1 (amino acids 894–907).

Figure 2. Age at DCM diagnosis.

Half of patients (50% were diagnosed during the first 6 mo of life including 7 patients (15.9%) that were diagnosed immediately at birth. DCM indicates dilated cardiomyopathy.

Figure 3. Mode of onset and clinical course.

At last follow‐up, 15 patients (36%) required a heart transplantation (n=14) or died (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, and 12 (29%) had a significant increase in left ventricular ejection fraction. ACE indicates angiotensin‐converting enzyme; DCM, dilated cardiomyopathy; FU, follow‐up; HF, heart failure; HT, heart transplantation; LVRR, left ventricular reverse remodeling; and MRA, mineralocorticoid receptor antagonist. *Asymptomatic includes patients diagnosed due to casual finding or in context of family screening.

Figure 4. Kaplan–Meier curve of incidence of ESHF.

Overall, 15 patients had an ESHF event during follow up, 14 in the form of HT and 1 as death due to HF. Event rate from diagnosis was established in 25.3% at 5 y. ESHF indicates end‐stage heart failure.

Figure 5. Kaplan–Meier curve of incidence of end‐stage heart failure according to NYHA at baseline.

NYHA showed the highest discrimination capacity (Harrell's C‐statistic=0.787). Patients in NYHA class III–IV had a 41.2% event rate at 2 y and 58.8% event rate at 5 y. ESHF indicates end‐stage heart failure; HR, hazard ratio; and NYHA, New York Heart Association.