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

    Greenberg     November 10, 2024 in News - 28 Minutes


    1. Introduction

    Hypoplastic left heart syndrome (HLHS) is a severe and complex congenital heart disease which is uniformly fatal early in life without surgical intervention. A three-stage surgical palliation, which is now the standard of care, allows many patients to live into adulthood. Despite these advances, many risk factors have been identified that affect both short- and long-term survival, including obstructive pulmonary venous return, restrictive or intact atrial septum, coronary artery abnormalities, tricuspid regurgitation, smaller ascending aorta size, premature birth, and HLHS associated with a genetic syndrome [1,2]. Surgical intervention for HLHS is palliative in nature, with many patients ultimately requiring heart transplantation. Although the cumulative risk of transplantation becomes higher as time goes on, transplant need can arise at any time following birth and at any stage of surgical reconstruction [3,4,5]. The identification of additional predictors that improve risk stratification would help inform clinical decisions regarding if, and when, to list a patient for cardiac transplant.
    We previously reported that rare, predicted damaging variants in the MYH6 gene were enriched in HLHS and associated with reduced cardiac transplant-free survival [6]. These findings were supported by our analysis of a control-matched subset [7]. We therefore sought to identify measurable functional consequences of MYH6 variants that could aid in improved transplant risk stratification of these patients, using more recent survival and imaging data from previously published cohorts [6,7] along with additional patients that have presented to our institution over the last five years.
    MYH6 encodes for α-myosin heavy chain (α-MHC), a key force-generating protein in cardiac muscle. MYH6 is expressed in the early developing heart and localizes predominantly to the atria during the first trimester of gestation [8]. Postnatal ventricles express primarily MYH7, which encodes for the β isoform of myosin heavy chain (β-MHC). Although HLHS is characterized by diminished ventricular size, the formation of the heart chambers is flow-mediated [9,10], and atrial contraction is thus essential for proper ventricular development.
    MYH6 continues to be the predominant isoform expressed in the atria postnatally, suggesting that MYH6 variants would continue to impact atrial function after birth. The need for transplant is primarily based on the right ventricular (RV) and tricuspid valve function, with consideration given to signs of end-organ damage, including renal disease, protein-losing enteropathy, and plastic bronchitis [3,4,11]. The functional status of the right atrium (RA) is not typically considered, even though the atria play multiple roles in cardiac output. During ventricular systole, the atria collect venous blood flow (‘reservoir’ function), then during early diastole they act as conduits for venous blood in transit to the ventricles (‘conduit’ function). In late ventricular diastole, the atria actively contract (atrial “kick”) to maximize the ventricular end diastolic volume, contributing up to 20–30% of cardiac output [12]. In patients with impaired ventricular function, including single-ventricle patients, the diastolic ventricular filling becomes more reliant on atrial kick.
    We hypothesized that MYH6 impairs RA contractility, ultimately resulting in decreased RV output and accelerating the failure of surgically-reconstructed HLHS hearts. We further hypothesized that RA dysfunction would present early, prior to detectable RV failure. To test this, we performed a retrospective echocardiogram analysis of pre-surgical RA function in HLHS patients with and without MYH6 variants. Atrial function was assessed via myocardial strain using semi-automated two-dimensional speckle-tracking echocardiography (2D-STE). Myocardial strain is a measure of tissue deformation and is defined as a change in myocardial fiber length relative to the baseline. 2D-STE calculates myocardial movement via ‘speckles’, naturally occurring acoustical markers in ultrasound. The movement of speckles within a tissue from one echo frame to the next allows them to be translated into myocardial velocity vectors [13].

    Table 1.
    Characteristics of MYH6 variants included in the study. Allele frequencies were obtained from the Genome Aggregation Database Genomes dataset (gnomAD) v4.1.0. Combined annotation-dependent depletion (CADD) scores are based on genome build GRCh38 (CADD v1.7).

    Table 1.
    Characteristics of MYH6 variants included in the study. Allele frequencies were obtained from the Genome Aggregation Database Genomes dataset (gnomAD) v4.1.0. Combined annotation-dependent depletion (CADD) scores are based on genome build GRCh38 (CADD v1.7).

    Study IDMYH6 VariantdbSNP IDAllele FrequencyCADDPreviously Reported
    R0735Q277Hrs1406604812.6 × 10−425.0Y [6,14,15]
    21_124A336Grs1385727906.8 × 10−523.7N
    07_155D383NN/ANot reported25.7Y [6]
    10_121S385Lrs7783191085.9 × 10−524.1Y [6]
    10_121M436VN/A6.2 × 10−724.9Y [6]
    07_067R443PN/ANot reported28.7Y [6,16]
    R_0622F469VN/ANot reported26.0N
    18_001K867Rrs1432842788.7 × 10−624.5N
    07_074K849-N/AN/AN/AY [6]
    R0121A936Vrs1998380242.7 × 10−424.6Y [6,17]
    10_249, 09_299A964Srs1449075222.2 × 10−424.7Y [6]
    07_082R1151Qrs7454066702.7 × 10−528.0Y [6]
    09_103A1298Vrs3685880521.4 × 10−425.9Y [6]
    09_152, 12_093T1379Mrs1456111858.6 × 10−431Y [6,18,19,20]
    11_003A1443Drs7275032342.0 × 10−426.2Y [6,14,19,21]
    12_234E1503VN/ANot reported35.0Y [6]
    09_204E1584Krs12803216392.5 × 10−628.7Y [6]
    07_026E1754Xrs3722706001.9 × 10−645.0Y [6]
    R0300K1840Rrs3736290591.1 × 10−428.2Y [6,22]

    2. Materials and Methods

    2.1. Study Population

    The cohort was retrospectively selected from all consenting patients with a primary diagnosis of HLHS who were seen at our institution prior to stage I palliation between the years 2000 and 2021. They all had whole-genome or whole-exome sequencing data available. Patients were first identified who carried rare, predicted damaging MYH6 variants, as defined by minor allele frequency <0.001 in both the Genome Aggregation Database Genomes dataset (gnomAD; v4.1.0) [23] and the Allele Frequency Aggregator dataset (ALFA; v20201027095038), as well as either a scaled combined annotation-dependent depletion (CADD) score >23.0 (GRCh38, v1.7) [24] or a prediction of “damaging” or “probably damaging” by either SIFT [25] or PolyPhen2 [26]. The variant information is summarized in Table 1. All known familial inheritance information concerning these variants has been previously published [6]. Three variants—MYH6R443P [6], MYH6E1503V [27], and MYH6E1584K [28]—segregate with congenital heart disease (CHD), including HLHS, in families.
    MYH6 variant carriers were matched to two controls based on aortic and mitral valve anatomy, sex when possible, era (i.e., year of birth), and stage I palliation surgical shunt type to allow for future longitudinal comparisons. Controls were selected from all the available HLHS patients with whole-genome or whole-exome sequencing showing the absence of any rare, predicted damaging MYH6 variant. Patients were excluded who had any chromosomal abnormality or who carried rare, predicted damaging variants in the MYH7 or DMD genes, as well as patients who had received any fetal intervention. All the available data from each patient’s electronic medical record were independently reviewed and verified by two separate individuals. Earlier outcomes for some patients in this cohort have been previously reported [6,7].

    2.2. Echocardiogram Acquisition

    All the echocardiograms were assessed retrospectively. Studies were obtained from awake patients shortly after birth, prior to any surgical intervention. The echocardiogram clip duration and frame rates varied based on age and quality of study.

    2.3. Myocardial Strain

    A 2D-STE analysis was completed on previously existing echocardiograms using TomTec Arena v4.20 (Philips Ultrasound Inc., Reedsville, PA, USA). For multi-beat clips with accompanying electrocardiograms (ECGs), TomTec automatically marked the cardiac cycle, with end-systole positioned at the completion of the T wave and end-diastole at the peak of the R wave. For single-beat clips and those without ECGs of sufficient quality, users manually set end-systole and end-diastole at the opening and closure of the AV valves, respectively. This method is consistent with the recommendations outlined in the most recent European Association of Cardiovascular Imaging (EACVI)/American Society of Echocardiography (ASE)/Industry Task Force to standardize deformation imaging consensus statements [29].

    All the measurements were obtained from the apical four-chamber view using a semi-automated tracking method. Users first delineated the endocardial border at end-diastole and the TomTec tracking algorithm was allowed to calculate myocardial deformation. The accuracy of the tracking was reviewed by a pediatric cardiology faculty member and if needed, the borders were adjusted manually. Global longitudinal strain (GLS) and time-plots for strain and strain rate (SR) were reported by TomTec.

    Atrial tracings extended upward from the lateral tricuspid valve annulus, across the roof of the atrium and returning to the septal annulus (Figure 1). Tracings excluded the atrial appendage and, as others have described [30], continued straight across the atrial septal defects present in most HLHS patients. From the atrial strain time-plots, strain during the conduit phase (AScd) was recorded as peak positive strain, strain during the contraction phase (ASct) was recorded as peak negative strain, and strain during the reservoir phase (ASr) was calculated as the difference between the two (AScd–ASct). From the atrial SR time-plots, SR during the contraction phase (ASRct) was recorded as peak negative SR, while SR during the reservoir phase (ASRr) was recorded as peak positive SR. Atrial SR during the conduit phase (ASRcd) was not obtained; as reported by others, two distinct negative peaks are not seen on the SR time-plots in neonates due to high heart rates and limited passive ventricular filling time [31].
    Ventricular tracings extended from the lateral tricuspid valve annulus, along the lateral free wall to the RV apex and across the interventricular septum to the septal annulus (Figure 1). Ventricular strain time-plots allowed for the measurement of systolic ventricular strain (VSs), recorded as peak negative strain. Systolic ventricular SR (VSRs), recorded as peak negative SR, and ventricular SR during early diastole (VSRed), recorded as peak positive SR, were obtained from ventricular SR time-plots.

    2.4. Statistical Analysis

    Poor outcomes were defined as the need for mechanical circulatory support, cardiac transplant, or death. Categorical variables are reported as N(%) and groups compared using an exact Fisher test. Continuous variables are reported as median (IQR), unless otherwise indicated, and compared using exact two-tailed nonparametric Mann-Whitney tests. Pearson correlation coefficients were calculated for the linear association of the strain parameters with heart rate, and two-tailed significance was obtained. A general linear model with a normal error link was used to look further at associations between strain and heart rate and the R2 was adjusted for these two variables. The 15-year event-free survival between the groups was compared using Kaplan-Meier curves, and the significance was evaluated using a logrank test. For all the analyses, p < 0.05 was considered significant but given the small sample size, we considered p < 0.1 to be a trend towards significance. No adjustment for multiple comparisons was made when examining our primary outcome of interest (ASct).

    3. Results

    3.1. Characteristics of the Study Cohort

    A total of 19 HLHS patients carrying MYH6 variants had echocardiograms available. Some 18 of these patients were matched to two controls each, while one variant carrier had a single control with an echocardiogram available for analysis. Given that the cases and controls were closely matched during the study design, the percentages of each sex, anatomical subtype, and stage I surgical shunt type were similar in each group (Table 2). While we were unable to match directly for the presence of restrictive or intact atrial septum, the overall percentages were similar between the groups (Table 2).

    To the extent possible in a retrospective study, controls were selected that were born in similar eras as variant carriers; the median time between the date of birth of cases and matched controls was 1.58 years (IQR 0.83, 2.42). The median age at the time of the pre-surgical echocardiogram was 0.0 days for both variant carriers (IQR 0.0, 2.0; maximum 7.0) and controls (IQR 0.0, 1.0; maximum 13.0). Most patients were in sinus rhythm at the time of the echocardiograms; a junctional rhythm was suspected in one patient but could not be confirmed. Most had heart rates within expected ranges for the newborn period (120–190 bpm); one was slightly bradycardic (102 bpm).

    The majority of the patients in both groups were not mechanically ventilated at the time of the echocardiograms (Table 2). Five (26.3%) MYH6 variant patients were intubated and mechanically ventilated at the time of imaging. An additional two (10.5%) MYH6 variant patients required intubation pre-stage I; however, records do not indicate whether this was prior to their echocardiograms. Seven control patients (18.9%) were intubated and mechanically ventilated at the time of imaging, though one of these patients was recorded as being “electively” intubated for transport. One control patient (2.7%) did not have records available stating the mode of breathing.

    3.2. Event-Free Survival

    The 15-year event-free survival analysis of this matched cohort showed a trend of decreased event-free survival in MYH6 variant carriers (p = 0.094, Figure 2). The median follow-up time for patients who did not meet the primary endpoint was 14.5 years (IQR 10.5, 18.5) for the overall cohort, 15.1 years (IQR 10.4, 18.0) for controls, and 14.4 years (IQR 10.8, 18.5) for MYH6 variant carriers.

    3.3. Right Atrial and Ventricular Strain Analyses

    The absolute values of RA ASct were significantly decreased in MYH6 variant carriers (−1.41%, IQR −2.13, −0.25) compared to controls (−3.53%, IQR −5.53, −1.28, p = 0.008; Table 3). RA ASRr also trended lower in variant carriers (1.06, (0.78, 1.43)%/s) compared to controls (1.23 (1.05, 1.55)%/s). While this difference did not reach statistical significance (p = 0.096), the small sample size suggests further investigation is needed in a larger cohort. No differences were found in RA GLS, AScd, ASr, or ASRct between the groups, and no differences were found in any RV strain indices between the groups.
    We identified no significant relationships between heart rate (HR) and RA GLS, RA ASct, RA ASRr, or RA ASRct in either group (Table 4). Significant positive correlations were found between HR with both RA AScd and RA ASr in MYH6 variant carriers only. In the general linear model with RA AScd as the outcome, RA AScd was significantly associated with the presence of an MYH6 variant (p = 0.031) and the interaction of a variant differed based on HR (p = 0.033) with an adjusted R2 = 0.035. This indicates that not only does the presence of an MYH6 variant have an effect on AScd, but that this effect varies with HR. We similarly assessed the relationship between RV strain indices and HR. Significant positive correlations were found between GLS, VSs, and VSRs with HR in controls; however, we found no significant relationships in MYH6 variant carriers (Table 4).

    4. Discussion

    4.1. Right Atrial Contractile Function

    In this study, we identified functional consequences associated with MYH6 variants, which are a known risk factor for decreased cardiac transplant-free survival in HLHS. Specifically, HLHS patients carrying MYH6 variants have lower RA ASct vs controls, indicating significantly impaired RA contractility (i.e., decreased atrial “kick”) in the absence of RV dysfunction. This suggests that reduced atrial “kick” may be a significant contributor to RV failure in surgically palliated HLHS patients with MYH6 variants. These findings are consistent with the predominant atrial localization of α-MHC and its function as a contractile protein, as well as mechanistic studies by our group and others showing impaired cardiomyocyte contractility associated with MYH6 variants [16,32,33].

    4.2. Right Atrial Conduit and Reservoir Function

    Previous characterization of pediatric atrial strain and SR indices report that AScd has an inverse relationship with HR [31]. Conversely, we found that in MYH6 variant carriers RA conduit and reservoir strain increased as HR increased, indicating RA distension both during atrial filling and during early ventricular filling after the opening of the tricuspid valve. Notably, we did not find statistically significant differences in RA reservoir or conduit strain when heart rate is not taken into account. When considering this in the context of impaired atrial contraction, we hypothesize that RA distension is secondary to the inability of the RA to increase its contractile activity and compensate for decreased passive ventricular filling time as HR increases. Given that single-ventricle patients are more reliant on the atrial contribution to ventricular filling when compared to healthy pediatric patients [30], impaired atrial contraction in MYH6 variant carriers is likely to be especially detrimental for cardiac function in this population.

    4.3. Impact of Right Ventricular Function

    It is important to consider that the atria are dynamic and adapt their function to maintain cardiac output in the presence of ventricular changes [34,35]. It is therefore possible that the RA dysfunction we observed in MYH6 variant carriers is secondary to early RV dysfunction (i.e., during fetal life). Recent studies of surgically palliated HLHS patients have shown that atrial reservoir strain at the time of pre-Glenn echocardiograms correlates with mortality or the need for cardiac transplant prior to Fontan [36], and the authors hypothesized that atrial dysfunction may be secondary to changes in ventricular diastolic function. A notable distinction is that their findings showed that atrial reservoir strain was associated with low RV GLS [36], while we did not identify significant differences in RV strain indices between the groups. Furthermore, RV VSRed was not correlated with HR in MYH6 variant carriers, which is inconsistent with ventricular stiffness and diastolic dysfunction as the primary pathology.
    We did identify that RV GLS, VSs, and VSRs were positively correlated with HR in controls only, which could indicate a primary ventricular contractile deficit in MYH6 variant carriers. Previous reports have found that RV VSs decreases with increasing HR in healthy children [37]. This could suggest that the relationship between RV strain and HR seen in our control patients may be an abnormal response. Unfortunately, studies are lacking that examine the relationship of RV strain and HR in the single-ventricle population, making it difficult to interpret our findings.

    4.4. Limitations

    Our study did have some notable limitations. Assessing echocardiograms obtained prior to any surgical intervention is our best opportunity to examine native RA mechanics, as once staged palliation begins many factors impact both atria and overall cardiac function, potentially confounding the influence of MYH6 variants. However, the retrospective nature of the study may have resulted in suboptimal echocardiogram views and variation in image quality over the years, including a lack of tricuspid color Doppler on many of the studies. While we were able to minimize some of these differences between the groups by control-matching based on approximate year of birth, this also limited our ability to match based on atrial restriction or account for the degree of tricuspid regurgitation.

    Our analysis also did not take into account differences in ventilation status between the groups. Mechanical ventilation impacts numerous aspects of cardiac hemodynamics, including right heart preload, afterload, and compliance [38,39], all of which must be considered when interpreting our RA and RV strain findings. Differences in the need for mechanical ventilation could also be a downstream effect of impaired cardiac function, though further studies are required to evaluate this hypothesis. Additionally, the small sample size may have limited the statistical power of our study and obscured potentially significant differences in RV function between the groups. Repeating these analyses in a larger cohort would help clarify this further.
    It is also important to consider that in silico measures of MYH6 variant pathogenicity cannot fully predict the functional impact. Further testing of specific MYH6 variants using in vitro and animal models is required to delineate which variants have meaningful phenotypic consequences on cardiomyocyte contractility. A more extensive discussion of currently published genetic and functional data of MYH6 variants, including those presented here, can be found in previous publications [7].

    5. Conclusions

    Our findings demonstrate atrial dysfunction associated with MYH6 variants in HLHS. HLHS patients with MYH6 variants have decreased atrial contractile strain, as well as an increase in reservoir and conduit strain with increasing HR. RV strain indices were not decreased in MYH6 variant carriers, consistent with a primary atrial phenotype.

    The confirmation of these findings in a larger cohort, along with longitudinal studies of atrial function in HLHS, are warranted to identify if RA dysfunction in MYH6 variant carriers is evident throughout the lifetime of these patients and, if so, its relationship to decreased transplant-free survival. Such studies will further elucidate if atrial dysfunction could be an informative prognostic consideration in HLHS patients with MYH6 variants and thus justify early genetic screening.

    Author Contributions

    M.Q.A., conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing—original draft, writing—review & editing; S.C., conceptualization, investigation, methodology, visualization, writing—original draft, writing—review & editing; P.M.S., formal analysis, methodology, writing—review & editing; J.M.J., conceptualization, methodology, resources, project administration, supervision; P.L., data curation, validation; P.C.F., conceptualization, methodology, resources, project administration, software; A.T.-M., conceptualization, funding acquisition, project administration, resources, supervision, writing—review & editing; M.E.M., conceptualization, funding acquisition, project administration, resources, supervision, writing—review & editing. All authors have read and agreed to the published version of the manuscript.

    Funding

    This study was supported by the MCW Advancing a Healthier Wisconsin Endowment, the MCW CTSI via NIH CTSA awards (UL1TR001436, 1TL1TR001437), the MCW Department of Surgery, and the Herma Heart Institute. MQA is a member of the MCW Medical Scientist Training Program, which is partially supported by a NIGMS training grant (T32-GM080202).

    Institutional Review Board Statement

    All the studies were performed in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments, as well as local and institutional ethical regulations. All the protocols were approved by the MCW Institutional Review Board (PRO ID #00047811, approval date 10 October 2023).

    Informed Consent Statement

    Written informed consent, and assent where applicable, was obtained from all participants for the collection and use of information (including deidentified genetic information, medical records and images, including echocardiograms, cardiac MRI, ECG, and Holter monitoring) for research purposes, including publication.

    Data Availability Statement

    Restrictions apply to the availability of these data. The data are restricted as they contain protected patient information.

    Acknowledgments

    We thank the families, physicians, and clinical care team of the Herma Heart Institute, including Tracy Geoffrion, MD, MPH, Megan Schloessing, and the HHI echocardiography research lab, Mary Krolikowski, Anne Laulederkind, Regina Cole, Mary Goetsch, MS, Huan-Ling Liang, MD, and Lisa Armitage for their support.

    Conflicts of Interest

    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).

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    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 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.
    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.

    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.

    Genes 15 01449 g002

    Table 2.
    Patient characteristics.

    Table 2.
    Patient characteristics.

    MYH6 Variant
    n = 19 (%)    		Control
    n = 37 (%)
    Sex
    Male9 (47.4)20 (54.1)
    Female10 (52.6)17 (45.9)
    Anatomy
    AA/MA10 (52.6)19 (51.4)
    AA/MS2 (10.5)4 (10.8)
    AS/MS7 (36.8)14 (37.8)
    RAS or IAS7 (36.8)12 (32.4)
    Respiratory Status
    Mechanical ventilation5 (26.3)7 (18.9)
    Room air or nasal cannula12 (63.2)29 (78.3)
    Unknown2 (10.5)1 (2.7)
    Stage I shunt type
    BTTS10 (52.6)19 (51.4)
    RVPAC (Sano)9 (47.4)18 (48.6)

    Table 3.
    RA and RV strain indices presented as median (IQR). Exact significance calculated using a two-sided Mann-Whitney U test.

    Table 3.
    RA and RV strain indices presented as median (IQR). Exact significance calculated using a two-sided Mann-Whitney U test.

    MYH6 Variant
    (N = 19)    		Control
    (N = 37)    		p-Value
    RA GLS (%)18.2 (15.0, 24.1)22.2 (14.9, 24.9)0.263
    RA AScd (%)26.4 (20.7, 31.2)27.0 (19.7, 34.4)0.810
    RA ASct (%)−1.41 (−2.13, −0.25)−3.53 (−5.53, −1.28)0.008 **
    RA ASr (%)28.5 (21.2, 33.2)31.0 (24.7, 37.5)0.302
    RA ASRr (%/s)1.06 (0.78, 1.43)1.23 (1.05, 1.55)0.096
    RA ASRct (%/s)−1.26 (−1.55, −0.99)−1.40 (−1.71, −1.13)0.198
    RV GLS (%)−12.5 (−15.0, −11.3)−12.5 (−14.4, −10.7)0.683
    RV VSs (%)−14.3 (−16.3, −12.9)−14.6 (−17.4, −11.4)0.201
    RV VSRs (%/s)−0.89 (−0.99, −0.77)−0.78 (−1.07, −0.66)0.127
    RV VSRed (%/s)28.5 (21.2, 33.2)31.0 (24.7, 37.5)0.302
    Heart rate (bpm)145 (138, 157)154 (142, 162)0.283

    Table 4.
    Correlations of RA and RV strain indices with heart rate, presented with two-sided significance.

    Table 4.
    Correlations of RA and RV strain indices with heart rate, presented with two-sided significance.

    MYH6 VariantControl
    Pearson Correlation (R)p-ValuePearson Correlation (R)p-Value
    RA GLS (%)0.2680.267−0.0440.796
    RA AScd (%)0.4690.043 *−0.1760.297
    RA ASct (%)−0.1480.546−0.2200.190
    RA ASr (%)0.4990.029 *−0.1020.547
    RA ASRr (%/s)0.3680.121−0.0470.783
    RA ASRct (%/s)−0.2350.3320.2740.100
    RV GLS (%)−0.0010.9970.3250.050 *
    RV VSs (%)−0.0690.7790.4190.010 *
    RV VSRs (%)−0.1270.6040.4100.012 *
    RV VSRed (%)−0.1000.685−0.2650.113

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