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. 2024 Nov 10;15(11):1449.
doi: 10.3390/genes15111449.

MYH6 Variants Are Associated with Atrial Dysfunction in Neonates with Hypoplastic Left Heart Syndrome

Melissa Quintanilla Anfinson  1 , Sara Creighton  2 , Pippa M Simpson  3 , Jeanne M James  4 , Phoebe Lim  1 , Peter C Frommelt  2 , Aoy Tomita-Mitchell  1 , Michael E Mitchell  1   5
Affiliations

MYH6 Variants Are Associated with Atrial Dysfunction in Neonates with Hypoplastic Left Heart Syndrome

Melissa Quintanilla Anfinson et al. Genes (Basel). .

Abstract

Background: MYH6 variants are the most well-known genetic risk factor (10%) for hypoplastic left heart syndrome (HLHS) and are associated with decreased cardiac transplant-free survival. MYH6 encodes for α-myosin heavy chain (α-MHC), a contractile protein expressed in the neonatal atria. We therefore assessed atrial function in HLHS patients with MYH6 variants. Methods: We performed a retrospective, blinded assessment of pre-stage I atrial function using 2D speckle-tracking echocardiography (2D-STE). Variant carriers were control-matched based on AV valve anatomy, sex, and birth year. Studies were obtained postnatally from awake patients prior to surgical intervention. Right atrial (RA) and right ventricular (RV) strain and strain rate (SR) were measured from the apical four-chamber view. Results: A total of 19 HLHS patients with MYH6 variants had echocardiograms available; 18 were matched to two controls each, and one had a single control. RA active strain (ASct) was decreased in variant carriers (-1.41%, IQR -2.13, -0.25) vs. controls (-3.53%, IQR -5.53, -1.28; p = 0.008). No significant differences were identified in RV strain between the groups. RA reservoir strain (ASr) and conduit strain (AScd) positively correlated with heart rate (HR) in MYH6 variant carriers only (ASr R = 0.499, p = 0.029; AScd R = 0.469, p = 0.043). RV global longitudinal strain (GLS) as well as RV systolic strain (VSs) and strain rate (VSRs) correlated with HR in controls only (GLS R = 0.325, p = 0.050; VSs R = 0.419, p = 0.010; VSRs R = 0.410, p = 0.012). Conclusions: We identified functional consequences associated with MYH6 variants, a known risk factor for poor outcomes in HLHS. MYH6 variant carriers exhibit impaired RA contractility despite there being no differences in RV function between variant carriers and controls. MYH6 variants are also associated with an ineffective RA reservoir and conduit function at high heart rates, despite preserved RV diastolic function. RA dysfunction and reduced atrial "kick" may therefore be a significant contributor to RV failure and worse clinical outcomes in HLHS patients with MYH6 variants.

Keywords: MYH6; atrial strain; congenital heart disease; hypoplastic left heart syndrome; speckle-tracking echocardiography.

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Conflict of interest statement

No author relationships with industry are directly related to the material in this publication. Other industry relationships of authors include: MEM, ATM are founders, major stockholders, board members, and receive research support from TAI Diagnostics. MEM, ATM are founders and stockholders of MD Interactive. MEM, ATM have relationships with GenDx (intellectual property) and Natera (research support, intellectual property).

Figures

Figure 1
Figure 1
Representative tracings and time-rate plots of atrial and ventricular myocardium in postnatal HLHS. AScd, conduit atrial strain; ASr, reservoir atrial strain; ASct, active/contractile atrial strain; ASRr, reservoir atrial strain rate; ASRct, active/contractile atrial strain rate; VSs, systolic ventricular strain; VSRs, systolic ventricular strain rate; and VSRed, early diastolic ventricular strain rate.
Figure 2
Figure 2
Kaplan-Meier curves comparing 15-year event-free survival in MYH6 variant carriers vs. controls. Shaded areas represent 95% confidence intervals. ‘+’ signs indicate censored patients.
See this image and copyright information in PMC

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