Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy—The Graz Hypertrophic Cardiomyopathy Registry
by
, , ,
Viktoria Höller
1,†, 
Heidelis Seebacher
2,†,
David Zach
1,
Nora Schwegel
1,
Klemens Ablasser
1,
Ewald Kolesnik
1,
Johannes Gollmer
1,
Gert Waltl
3,
Peter P. Rainer
1,
Sarah Verheyen
2,
Andreas Zirlik
1 and
Nicolas Verheyen
1,* 1
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
2
Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, 8010 Graz, Austria
3
Division of Cardiology, Department of Internal Medicine, State Hospital (LKH) Graz II, 8020 Graz, Austria
*
Author to whom correspondence should be addressed.
†
Contributed equally.
Genes 2021, 12(10), 1469; https://doi.org/10.3390/genes12101469
Submission received: 20 August 2021
/
Revised: 21 September 2021
/
Accepted: 22 September 2021
/
Published: 23 September 2021
(This article belongs to the Collection Genotype-Phenotype Study in Disease)
Abstract
:Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 (n = 39) or MYH7 (n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: −16.9 ± 0.6% vs. −17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (−24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.
1. Introduction
Sarcomeric hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease affecting 1 in 200 to 500 people. While left ventricular hypertrophy is considered the hallmark of sarcomeric HCM, also the right ventricle can be affected. The clinical spectrum ranges from normal to severely impaired myocardial function leading to restrictive cardiomyopathy [1]. Pathogenic or likely pathogenic variants in sarcomere protein encoding genes can be identified in 40–60% of adolescents and adults affected by HCM. MYBPC3 (encoding cardiac myosin binding protein—C, cMyBPC) and MYH7 (encoding β cardiac myosin heavy chain) account for the majority of cases [2,3,4].
Accumulating evidence suggests that MYH7 mutations are associated with an earlier onset of symptoms [5,6,7], more pronounced hypertrophy and poorer prognosis when compared to MYBPC3 [8,9]. Both, MYH7 and MYBPC3 mutations affect the thick filament of the sarcomere [8], but via differing pathways. Regarding MYH7, more than 95% of known disease causing variants are missense mutations leading to integration of altered myosin into the sarcomere [10]. Most MYBPC3 mutations lead to diminished levels of cMyBPC in the sarcomere resulting in haploinsufficiency [11]. Mutations in both genes cause hyperdynamic contraction and poor relaxation of the myocardium [11]. Previous studies failed in the majority to demonstrate phenotypic differences between MYBPC3 and MYH7 mutation carriers.
Some imaging studies were suggestive of a more severe phenotype in individuals carrying a pathogenic genetic variant in MYH7 mutations compared to MYBPC3, although differences were often marginal and non-significant [3,8,12]. Other studies found no significant differences with regard to parameters of left ventricular (LV) function and structure, and myocardial scar formation [13,14]. Most studies were, however, limited by their lack to assess myocardial deformation analysis which is superior to standard echocardiography in detecting myocardial scar formation [15]. Moreover, no study has yet reported on association between genotype and right ventricular deformation in sarcomeric HCM.
Therefore, the aim of the present study was to compare echocardiographic characteristics applying myocardial deformation analysis of both the left and the right ventricle, on top of standard echocardiographic parameters in MYH7- and MYBPC3-associated HCM.
2. Materials and Methods
2.1. Design and Study Population
This is a cross-sectional analysis of the Graz HCM Registry (EC-No 30-286 ex 17/18). The Graz HCM Registry is a prospective cohort study launched in February 2019 and includes all patients aged over 18 years who are admitted to the HCM outpatient clinic of the Department of Cardiology of the Medical University of Graz, and provide written informed consent for participation. Registry procedures include a systematic transthoracic echocardiographic examination (TTE), a 12-lead electrocardiogram (ECG) and a structured patient interview.
For the present study we included participants with genetically proven sarcomeric HCM [2]. Patients were excluded if no echocardiographic study recorded within 6 months before or after registry inclusion was judged adequate of LV speckle tracking analysis. Patients were enrolled between February 2019 and June 2021. Clinical characteristics were assessed at the day of echocardiographic examination. 12-lead-ECG, laboratory analysis, and medical history were in most cases assessed on the day of TTE, but at least during a period of 6 months before or after the TTE.
2.2. Clinical Characteristics and Medical History
Clinical and medication history were systematically assessed during the patient interview at registry inclusion and complemented using medical records. NYHA class > II was defined as breathlessness, fatigue or palpitations at less than ordinary activities, e.g., at walking distance less than 1000 m or walking uphill [16]. Sarcomeric HCM was defined as proven mutation either in MYBPC3 or MYH7 classified as pathogenic or likely pathogenic and enddiastolic left ventricular wall thickness of ≥13 mm evidenced by TTE [2,17]. Patients carrying mutations in other sarcomere genes were omitted. Left ventricular outflow tract (LVOT) obstruction was defined as maximal left ventricular outflow tract gradient ≥ 30 mmHg either at rest or during provocations such as Valsalva maneuver or bicycle stress testing [18]. Septal reduction therapy was defined as either surgical myectomy or percutaneous transluminal septal myocardial ablation (PTSMA).
2.3. Genetic Analysis
The results of performed genetic analyses were collected in the Graz HCM Registry and were retrospectively analyzed. Genetic testing had been performed with DNA from peripheral blood for routine clinical care at different diagnostic laboratories. Panel analyses were used to identify the causal variants in the index patients. Sanger sequencing was used for segregation analysis in family members. Only patients with a confirmed pathogenic or likely pathogenic mutation in MYBPC3 and MYH7 were included in the study (Tables S1–S3). Variant classification followed international guidelines for the interpretation of sequence variants [19].
2.4. Echocardiographic Assessment and Variables
All patients were examined at rest using Siemens Acuson SC 2000 and a 4Z1 transducer (Siemens AG, Erlangen, Germany). An ECG was recorded during each study to define end-diastole (ED) and end-systole (ES). Images and cine-loops with frame rates from 40 to 80 Hz were stored and digitally archived in IntelliSpace Cardiovascular (ISCV, Philips, Eindhoven, The Netherlands) [20]. All echocardiography derived parameters used in the present study are listed in Table 1. Standard echocardiographic and Doppler measurements were assessed according to EACVI recommendations [21,22,23]. Maximum ED interventricular septum thickness (IVSEDd) was measured in the apical four-chamber view at basal, midventricular and apical levels, respectively.
2D speckle-tracking echocardiography (2D STE) was performed by experienced investigators (D.Z., N.S.) who were blinded to patients’ clinical characteristics, using the vendor-independent post-processing software TomTec-Arena including 2D Cardiac Performance Analysis (TomTec Imaging Systems, Munich, Germany). Cine-loops with the best image quality were selected for 2D STE. In patients with atrial fibrillation, special care was taken to choose cardiac cycles of similar duration. If tracking did not match the visual impression of wall motion, contours were readjusted until optimal tracking was achieved [24].
For the present study, we focused on endocardial strain analysis. LV global longitudinal strain (LV GLS) was calculated using the entire endocardial line length while computing LV deformation from the apical four-, three- and two-chamber views; conducted in two separate cardiac cycles whenever possible and reported as mean values. The endocardium was tracked as the region of interest using two different methods, once automatically generated (i.e., LV GLS auto) and once user-defined (i.e., LV GLS 2DCPA) [17]. Additionally, endomyocardial contouring by 2D Cardiac Performance Analysis was used to calculate ES and ED volumes of each apical view to subsequently compute a triplane ejection fraction of the left ventricle (LVEF) and to determine a triplane left ventricular basal ED diameter (LVEDd basal).
Right ventricular (RV) longitudinal strain was calculated by averaging peak longitudinal systolic strain values of equal segment lengths of the free wall and septum (six segments, i.e., RV4CLS) as well as the free wall only (three segments, i.e., RVFWSL); obtained in the apical four-chamber view. ED was defined by tricuspid valve closure and ES as the moment at which the RV was at its smallest [25,26]. If feasible, measurements were performed in three different cardiac cycles and reported as mean values.
2.5. Statistical Analysis
Categorical variables were expressed as counts (percentages), continuous variables were shown as mean ± standard deviation (SD) in case of normal distribution or as medians with interquartile range if non-normally distributed. Distribution of variables was evaluated by test of Kolmogorov-Smirnov, kurtosis, skewness, concordance between the mean and median, and visual inspection. For univariate group comparisons, we used Mann-Whitney U test, Student’s t-test or Chi-Square test, as appropriate.
In order to compare echocardiography derived parameters between MYBPC3 and MYH7 mutation carriers, analyses of covariance (ANCOVA) were used and adjusted for potentially confounding parameters including age, sex and history of septal reduction therapy. Means are reported as estimated marginal means and standard error derived from multivariate ANCOVA.
Homogeneity of regression slopes was not violated with regard to the dependent variable, as the interaction terms were not statistically significant (p > 0.05). The residuals were normally distributed, as determined by the Kolmogorov-Smirnov test (p > 0.05). The assumptions of homogeneity of variances were found to be satisfied, as assessed by Levene’s test (p > 0.05).
For all statistical analysis IBM SPSS Statistics Version 26 was used. The significance level α was set at 5%. Due to the exploratory character of the study we did not adjust for multiple testing.
3. Results
The cohort comprised 57 patients, including 39 (68%) with MYBPC3 mutation and 18 (32%) with MYH7 mutation. There was one patient with two disease causing mutations in MYBPC3 and one patient with a disease-causing mutation in MYBPC3 and MYH6. In 10 patients with MYBPC3 mutation and in six patients with MYH7 mutation, there was at least one additional variant of unknown significance (in MYH6, MYLK2, TTN, FLNC, RYR2, MYO6, TNNT2, MYPN, ILK, COX15, VCL, respectively).
3.1. Clinical Characteristics
Mean age was 49.1 ± 15.2 and 28 patients (49.1%) were females. Patients with MYBPC3 mutation were significantly older than those with MYH7 mutation (51.8 ± 14.4 vs. 41.4 ± 14.0 years; p = 0.013) and were less often female (n = 16, 41% vs. n = 12, 67%; p = 0.072). Patients carrying a MYBPC3 mutation had a lower estimated glomerular filtration rate (eGFR; 80.6 ± 22.4 vs. 100.6 ± 31.6 mL/min/1.73 m; p = 0.008) and were more often treated with a loop diuretic (21% vs. 0%; p = 0.038). Fifteen MYBPC3 mutation carriers had a previous implantation of an implantable cardioverter-defibrillator (ICD) compared with 0 patients carrying a MYH7 mutation (39% vs. 0%; p = 0.002). Nine patients received an ICD for primary prevention, and six patients for secondary prevention after survived sudden cardiac death (SCD). One SCD survivor with MYH7 mutation had refused ICD implantation for personal reasons. Atrial fibrillation was more common in MYBPC3 mutation carriers (31% vs. 6%; p = 0.035). Clinical characteristics are listed in more detail in Table 2.
3.2. Echocardiographic Parameters
Using analyses of covariates (ANCOVA), there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to LV GLS (estimated marginal means ± standard error: −16.9 ± 0.6 vs.−17.3 ± 0.9; p = 0.807), as illustrated in Figure 1. The LV ejection fraction (Simpson method) was slightly lower in MYBPC3 mutation carriers when compared to MYH7 mutation carriers without reaching statistical significance (53.03 ± 1.2 vs. 55.4 ± 1.8; p = 0.338). Parameters of LV structure were similar between the groups.
The mitral annular early diastolic velocity (e′ average) was significantly higher in the MYBPC3 group (8.5 ± 0.4 vs. 6.8 ± 0.6 cm/s; p = 0.026), but in relation to the transmitral early diastolic velocity (E/e′) no significant difference could be observed (p = 0.630). The mean left atrial volume index (LAVi) was similar between both groups (MYBPC3 54.3 ± 4.7, MYH7 50.1 ± 7.2; p = 0.637), as shown in Figure 2.
RV 6-segments endocardial strain was similar between MYBPC3 and MYH7 mutation carriers (−24.3 ± 1.0 vs. 26.3 ± 1.5; p = 0.285). Fractional area change of the right ventricle (RVFAC) showed significantly lower values in the MYBPC3 cohort (43.7 ± 1.7 vs. 52.4 ± 2.5; p = 0.007). Tricuspid annular plane systolic excursion (TAPSE) showed similar values in both groups (see Figure 3). All findings are resumed in Table 3.
4. Discussion
This is the first study describing detailed genotype-phenotype correlations in sarcomeric HCM focusing on myocardial deformation markers of both RV and LV. There were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to LV and RV longitudinal strain, respectively. In multivariate statistical models, only RVFAC and e’ were significantly different. However, while MYBPC3 mutation carriers had lower RVFAC suggesting a poorer RV function, they presented with higher e’ indicating better LV relaxation. In light of this ambiguity, these findings may be interpreted as effects of chance rather than as results of phenotypic differences related to the underlying mutations. The higher rate of ICD implantations in the MYBPC3 group may have confounded these associations as well.
The reason for the suggestively earlier onset of symptoms, worse prognosis and more pronounced hypertrophy in MYH7 mutations [5,6,7,8,9] could be explained by functional differences between the proteins coded by MYBPC3 and MYH7. Cycling interaction between actin and myosin drives sarcomeric contraction through sliding of thick and thin filaments past one another, creating force that allows cardiomyocytes to contract and relax. Cardiac MyBPC (cMyBPC) regulates myocardial contractility, with reduced cMyBPC levels leading to hypercontractility and impaired relaxation. MYBPC3 mutations are supposed to cause HCM by haploinsufficiency. Myosin is a mechanoenzyme that drives ventricular contraction and produces force when binding actin and hydrolyzing ATP [4]. Most HCM causing MYH7 mutations cluster between residues 181 and 937, forming the myosin head domain and approximately 20% are located in the coiled coil region forming the thick filament [27]. Mutant myosins show altered parameters of myocardial contraction like actin gliding velocity, intrinsic force production, cross—bridge cycling kinetics, calcium sensitivity of force generation and acto-myosin ATPase activity leading to hypercontractility and impaired relaxation [27,28,29,30]. Consistent with previous results [31], causal MYH7 variants in our cohort were predominantly missense mutations (see Table S3).
Pathogenic variants in MYBPC3 are predominantly truncating [7,32,33], which is in accordance with our results. Causal MYBPC3 variants in our cohort were primarily frameshift and splice site mutations (see Table S1). Only a few probands had disease causing missense mutations and there was one proband with an in-frame deletion and one with a nonsense mutation, respectively (see Tables S1 and S2). MYBPC3-associated HCM shows a later disease onset with a variability in the rate of progression even within a family, influenced by lifestyle, environment and other genetic factors [5,34]. The later age of onset is discussed as explanation for a relatively high proportion of founder mutations. All of them result in a shortened cMyBPC. Members of two families of our cohort carry a Dutch founder mutation (c.2864_2865delCT) [33]. A Tuscany founder mutation (c.772G > A) was detected in members of five families of our cohort [35].
Our results showed a higher age of disease onset in MYBPC3 patients. This is in line with a recent meta-analysis including 51 studies with 7675 HCM patients, where mutations in MYH7 were associated with earlier age of onset and higher risk of sudden cardiac death when compared to MYBPC3 [9]. In contrast, an earlier meta–analysis comprising 18 studies with 2459 patients found no differences in terms of symptoms, age of onset and grade of left ventricular hypertrophy between MYBPC3 and MYH7 mutation carriers [36].
Interestingly, MYBPC3 mutations carriers had significantly more often a history of ICD implantation. This is not in line with other and larger studies attributing a higher risk of SCD to MYH7 [8,9]. Patients with missense mutations affecting the actin binding site or the head–rod portion of β MHC showed decreased survival [37]. For instance, the p.Arg453Cys mutation in MYH7 is associated with a high incidence of end-stage heart failure and premature death [38]. Similarly, a significantly higher proportion of the MYBPC3 group had history of atrial fibrillation which is not in line with previous studies [9,39,40]. Both of these controversial observations are likely a consequence of referral bias in a tertiary HCM care center which is a well-known phenomenon in epidemiological research on HCM [41].
Only a few studies compared echocardiographic parameters between HCM genotypes although none explicitly reported results of RV myocardial deformation analyses. One recent multicenter study including 63 adult individuals evaluated the association between mutations in both genes and phenotypes in patients with sarcomeric HCM. They found that patients carrying a MYH7 mutation were similar to MYBPC3 carriers in the majority of measured echocardiographic parameters. Only systolic anterior motion of the mitral valve and mitral valve calcification were significantly more common in MYH7 mutation carriers [8]. It is well accepted that analysis of myocardial deformation markers is superior to standard echocardiographic parameters in detecting scar formation [15], predicting arrhythmias [42] and cardiovascular outcomes in HCM [43]. Evidence on differences of myocardial deformation markers between distinct HCM susceptibility genes is scarce. One previous study found that LV strain is similar between MYBPC3 and MYH7 mutation carriers. In this study the authors concluded that LV morphology rather than genotype predicts myocardial deformation markers in HCM [44]. However, RV myocardial deformation analyses were not included in their report.
Particular strengths of our study include its novelty, since myocardial deformation, particularly of the RV, has not been sufficiently investigated in patients with sarcomeric HCM. A further strength of our study is the high quality of strain measurements which were performed by blinded investigators analyzing several cine loops per patient.
Limitations of our study include the relatively low sample size and the single-center design. Moreover, characteristics of our cohort may be confounded by referral bias which may be inherent to our tertiary care setting, although we performed multivariate analysis to minimize this bias. Nevertheless, results may not be generalizable to other HCM populations.
5. Conclusions
Echocardiographic myocardial deformation parameters of both RV and LV were similar between MYBPC3 and MYH7 mutation carrying individuals with sarcomeric HCM. Myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/genes12101469/s1, Table S1: Truncating pathogenic or likely pathogenic MYBPC3 (NM_000256.3) mutations, Table S2: Pathogenic or likely pathogenic MYBPC3 (NM_000256.3) missense mutations, Table S3: Pathogenic or likely pathogenic MYH7 (NM_000257.4) mutations.
Author Contributions
Conceptualization, N.V., V.H. and H.S.; methodology, V.H., H.S., D.Z., N.S. and N.V.; validation, S.V. and N.V.; formal analysis, V.H. and N.V.; investigation, V.H., H.S., D.Z. and N.S.; resources, N.V.; writing—original draft preparation, V.H., H.S., D.Z., N.S. and N.V.; writing—review and editing, E.K., K.A., P.P.R., A.Z., N.V., S.V., J.G. and G.W.; supervision, N.V. and S.V.; project administration, V.H. and N.V.; funding acquisition, N.V. All authors have read and agreed to the published version of the manuscript.
Funding
V.H. was employed by funding from the Medical University of Graz (START Grant 2020). The Graz HCM Registry was supported by a General Research Grant from Pfizer Inc. (New York, NY, USA).
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Medical University of Graz (Ec-No EC-No 30-286 ex 17/18, date of approval 28 June 2018).
Informed Consent Statement
Informed consent was obtained from all patients involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Acknowledgments
We would like to thank all participating patients who consented to participate in the Graz HCM Registry. We would like to thank the Doctoral School “Translational Molecular and Cellular Biosciences” of the Medical University Graz for its support.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Semsarian, C.; Ingles, J.; Maron, M.S.; Maron, B.J. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J. Am. Coll. Cardiol. 2015, 65, 1249–1254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Elliott, P.M.; Anastasakis, A.; Borger, M.; Borggrefe, M.; Cecchi, F.; Charron, P.; Hagege, A.; Lafont, A.; Limongelli, G.; Mahrholdt, H.; et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur. Heart J. 2014, 35, 2733–2779. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.; Yang, F.; Liu, W.; Sun, J.; Han, Y.; Li, D.; Gkoutos, G.V.; Zhu, Y.; Chen, Y. Radiomic Analysis of Native T 1 Mapping Images Discriminates Between MYH7 and MYBPC3 -Related Hypertrophic Cardiomyopathy. J. Magn. Reson. Imaging 2020, 52, 1714–1721. [Google Scholar] [CrossRef] [PubMed]
- Toepfer, C.N.; Wakimoto, H.; Garfinkel, A.C.; McDonough, B.; Liao, D.; Jiang, J.; Tai, A.C.; Gorham, J.M.; Lunde, I.G.; Lun, M.; et al. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci. Transl. Med. 2019, 11, eaat1199. [Google Scholar] [CrossRef] [PubMed]
- Adalsteinsdottir, B.; Burke, M.; Maron, B.J.; Danielsen, R.; Lopez, B.; Diez, J.; Jarolim, P.; Seidman, J.; Seidman, C.E.; Ho, C.Y.; et al. Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers. Open Heart 2020, 7, e001220. [Google Scholar] [CrossRef] [Green Version]
- Geske, J.B.; Ong, K.C.; Siontis, K.C.; Hebl, V.B.; Ackerman, M.J.; Hodge, D.O.; Miller, V.M.; Nishimura, R.A.; Oh, J.K.; Schaff, H.; et al. Women with hypertrophic cardiomyopathy have worse survival. Eur. Heart J. 2017, 38, 3434–3440. [Google Scholar] [CrossRef] [Green Version]
- Sabater-Molina, M.; Pérez-Sánchez, I.; Del Rincón, J.H.; Gimeno, J. Genetics of hypertrophic cardiomyopathy: A review of current state. Clin. Genet. 2017, 93, 3–14. [Google Scholar] [CrossRef]
- Velicki, L.; Jakovljevic, D.G.; Preveden, A.; Golubovic, M.; Bjelobrk, M.; Ilic, A.; Stojsic, S.; Barlocco, F.; Tafelmeier, M.; Okwose, N.; et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy. BMC Cardiovasc. Disord. 2020, 20, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Sedaghat-Hamedani, F.; Kayvanpour, E.; Tugrul, O.F.; Lai, A.; Amr, A.; Haas, J.; Proctor, T.; Ehlermann, P.; Jensen, K.; Katus, H.A.; et al. Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: A meta-analysis on 7675 individuals. Clin. Res. Cardiol. 2017, 107, 30–41. [Google Scholar] [CrossRef]
- Walsh, R.; Rutland, C.; Thomas, R.; Loughna, S. Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations. Cardiology 2010, 115, 49–60. [Google Scholar] [CrossRef]
- Helms, A.S.; Tang, V.T.; O’Leary, T.S.; Friedline, S.; Wauchope, M.; Arora, A.; Wasserman, A.; Smith, E.D.; Lee, L.M.; Wen, X.W.; et al. Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy. JCI Insight 2020, 5. [Google Scholar] [CrossRef] [Green Version]
- Lopes, L.R.; Brito, D.; Belo, A.; Cardim, N. Genetic characterization and genotype-phenotype associations in a large cohort of patients with hypertrophic cardiomyopathy—An ancillary study of the Portuguese registry of hypertrophic cardiomyopathy. Int. J. Cardiol. 2018, 278, 173–179. [Google Scholar] [CrossRef] [PubMed]
- Viswanathan, S.K.; Sanders, H.K.; McNamara, J.W.; Jagadeesan, A.; Jahangir, A.; Tajik, A.J.; Sadayappan, S. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS ONE 2017, 12, e0187948. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weissler-Snir, A.; Hindieh, W.; Gruner, C.; Fourey, D.; Appelbaum, E.; Rowin, E.; Care, M.; Lesser, J.R.; Haas, T.S.; Udelson, J.E.; et al. Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. Circ. Cardiovasc. Imaging 2017, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pagourelias, E.D.; Mirea, O.; Duchenne, J.; Unlu, S.; Van Cleemput, J.; Papadopoulos, C.E.; Bogaert, J.; Vassilikos, V.P.; Voigt, J.-U. Speckle tracking deformation imaging to detect regional fibrosis in hypertrophic cardiomyopathy: A comparison between 2D and 3D echo modalities. Eur. Heart J.-Cardiovasc. Imaging 2020, 21, 1262–1272. [Google Scholar] [CrossRef] [PubMed]
- Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.F.; Coats, A.J.S.; Falk, V.; González-Juanatey, J.R.; Harjola, V.-P.; Jankowska, E.A.; et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2016, 37, 2129–2200. [Google Scholar] [CrossRef]
- Voigt, J.-U.; Pedrizzetti, G.; Lysyansky, P.; Marwick, T.H.; Houle, H.; Baumann, R.; Pedri, S.; Ito, Y.; Abe, Y.; Metz, S.; et al. Definitions for a common standard for 2D speckle tracking echocardiography: Consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur. Heart J.-Cardiovasc. Imaging 2014, 16, 1–11. [Google Scholar] [CrossRef]
- Ommen, S.R.; Mital, S.; Burke, M.A.; Day, S.M.; Deswal, A.; Elliott, P.; Evanovich, L.L.; Hung, J.; Joglar, J.A.; Kantor, P.; et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy: Executive Summary. J. Am. Coll. Cardiol. 2020, 76, 3022–3055. [Google Scholar] [CrossRef]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–423. [Google Scholar] [CrossRef] [PubMed]
- Mor-Avi, V.; Lang, R.M.; Badano, L.; Belohlavek, M.; Cardim, N.M.; Derumeaux, G.; Galderisi, M.; Marwick, T.; Nagueh, S.F.; Sengupta, P.P.; et al. Current and Evolving Echocardiographic Techniques for the Quantitative Evaluation of Cardiac Mechanics: ASE/EAE Consensus Statement on Methodology and Indications: Endorsed by the Japanese Society of Echocardiography. J. Am. Soc. Echocardiogr. 2011, 24, 277–313. [Google Scholar] [CrossRef]
- Lang, R.M.; Badano, L.; Mor-Avi, V.; Afilalo, J.; Armstrong, A.; Ernande, L.; Flachskampf, F.A.; Foster, E.; Goldstein, S.A.; Kuznetsova, T.; et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur. Heart J.-Cardiovasc. Imaging 2015, 16, 233–271. [Google Scholar] [CrossRef] [PubMed]
- Nagueh, S.F.; Smiseth, O.A.; Appleton, C.P.; Byrd, B.F.; Dokainish, H.; Edvardsen, T.; Flachskampf, F.A.; Gillebert, T.C.; Klein, A.L.; Lancellotti, P.; et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur. Heart J.-Cardiovasc. Imaging 2016, 17, 1321–1360. [Google Scholar] [CrossRef] [PubMed]
- Rudski, L.G.; Lai, W.W.; Afilalo, J.; Hua, L.; Handschumacher, M.; Chandrasekaran, K.; Solomon, S.D.; Louie, E.K.; Schiller, N.B. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the American Society of Echocardiography: Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J. Am. Soc. Echocardiogr. 2010, 23, 685–713. [Google Scholar] [CrossRef] [PubMed]
- Sugimoto, T.; Dulgheru, R.; Bernard, C.; Ilardi, F.; Contu, L.; Addetia, K.; Caballero, L.; Akhaladze, N.; Athanassopoulos, G.D.; Barone, D.; et al. Echocardiographic reference ranges for normal left ventricular 2D strain: Results from the EACVI NORRE study. Eur. Heart J.-Cardiovasc. Imaging 2017, 18, 833–840. [Google Scholar] [CrossRef]
- Badano, L.P.; Kolias, T.J.; Muraru, D.; Abraham, T.P.; Aurigemma, G.; Edvardsen, T.; D’Hooge, J.; Donal, E.; Fraser, A.G.; Marwick, T.; et al. Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: A consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur. Heart J.-Cardiovasc. Imaging 2018, 19, 591–600. [Google Scholar] [CrossRef]
- Badano, L.P.; Muraru, D.; Parati, G.; Haugaa, K.; Voigt, J.-U. How to do right ventricular strain. Eur. Heart J.-Cardiovasc. Imaging 2020, 21, 825–827. [Google Scholar] [CrossRef]
- Kraft, T.; Montag, J. Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy. Pflügers Arch.-Eur. J. Physiol. 2019, 471, 719–733. [Google Scholar] [CrossRef]
- Moore, J.R.; Leinwand, L.; Warshaw, D.M. Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. Circ. Res. 2012, 111, 375–385. [Google Scholar] [CrossRef] [Green Version]
- Adhikari, A.S.; Kooiker, K.B.; Sarkar, S.S.; Liu, C.; Bernstein, D.; Spudich, J.A.; Ruppel, K.M. Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin. Cell Rep. 2016, 17, 2857–2864. [Google Scholar] [CrossRef]
- Roest, A.S.V.; Liu, C.; Morck, M.M.; Kooiker, K.B.; Jung, G.; Song, D.; Dawood, A.; Jhingran, A.; Pardon, G.; Ranjbarvaziri, S.; et al. Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state. Proc. Natl. Acad. Sci. USA 2021, 118. [Google Scholar] [CrossRef]
- Waldmüller, S.; Erdmann, J.; Binner, P.; Gelbrich, G.; Pankuweit, S.; Geier, C.; Timmermann, B.; Haremza, J.; Perrot, A.; Scheer, S.; et al. Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: Results from the German Competence Network Heart Failure. Eur. J. Heart Fail. 2011, 13, 1185–1192. [Google Scholar] [CrossRef]
- Niimura, H.; Bachinski, L.L.; Sangwatanaroj, S.; Watkins, H.; Chudley, A.E.; McKenna, W.; Kristinsson, A.; Roberts, R.; Sole, M.; Maron, B.J.; et al. Mutations in the Gene for Cardiac Myosin-Binding Protein C and Late-Onset Familial Hypertrophic Cardiomyopathy. N. Engl. J. Med. 1998, 338, 1248–1257. [Google Scholar] [CrossRef] [PubMed]
- Christiaans, I.; Nannenberg, E.A.; Dooijes, D.; Jongbloed, R.J.E.; Michels, M.; Postema, P.G.; Majoor-Krakauer, D.; Wijngaard, A.V.D.; Mannens, M.M.A.M.; van Tintelen, J.P.; et al. Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands. Neth. Heart J. 2010, 18, 248–254. [Google Scholar] [CrossRef]
- Alders, M.; Jongbloed, R.; Deelen, W.; Wijngaard, A.V.D.; Doevendans, P.A.F.M.; Cate, F.T.; Regitz-Zagrosek, V.; Vosberg, H.-P.; Van Langen, I.; Wilde, A.A.M.; et al. The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands. Eur. Heart J. 2003, 24, 1848–1853. [Google Scholar] [CrossRef] [Green Version]
- Carrier, L.; Mearini, G.; Stathopoulou, K.; Cuello, F. Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology. Gene 2015, 573, 188–197. [Google Scholar] [CrossRef]
- Lopes, L.; Rahman, M.S.; Elliott, P.M. A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart 2013, 99, 1800–1811. [Google Scholar] [CrossRef] [PubMed]
- Woo, A. Mutations of the myosin heavy chain gene in hypertrophic cardiomyopathy: Critical functional sites determine prognosis. Heart 2003, 89, 1179–1185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tower-Rader, A.; Desai, M.Y. Phenotype–Genotype Correlation in Hypertrophic Cardiomyopathy. Circ. Cardiovasc. Imaging 2017, 10. [Google Scholar] [CrossRef] [Green Version]
- Bongini, C.; Ferrantini, C.; Girolami, F.; Coppini, R.; Arretini, A.; Targetti, M.; Bardi, S.; Castelli, G.; Torricelli, F.; Cecchi, F.; et al. Impact of Genotype on the Occurrence of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. Am. J. Cardiol. 2016, 117, 1151–1159. [Google Scholar] [CrossRef]
- Lee, S.-P.; Ashley, E.A.; Homburger, J.; Caleshu, C.; Green, E.M.; Jacoby, D.; Colan, S.D.; Arteaga-Fernández, E.; Day, S.M.; Girolami, F.; et al. Incident Atrial Fibrillation Is Associated with MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy. Circ. Heart Fail. 2018, 11, e005191. [Google Scholar] [CrossRef]
- Maron, B.J.; Casey, S.A.; Poliac, L.C.; Gohman, T.E.; Almquist, A.K.; Aeppli, D.M. Clinical Course of Hypertrophic Cardiomyopathy in a Regional United States Cohort. JAMA 1999, 281, 650–655. [Google Scholar] [CrossRef] [PubMed]
- Haland, T.F.; Almaas, V.M.; Hasselberg, N.E.; Saberniak, J.; Leren, I.S.; Hopp, E.; Edvardsen, T.; Haugaa, K.H. Strain echocardiography is related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy. Eur. Heart J.-Cardiovasc. Imaging 2016, 17, 613–621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tower-Rader, A.; Mohananey, D.; To, A.; Lever, H.M.; Popovic, Z.B.; Desai, M.Y. Prognostic Value of Global Longitudinal Strain in Hypertrophic Cardiomyopathy. JACC Cardiovasc. Imaging 2018, 12, 1930–1942. [Google Scholar] [CrossRef] [PubMed]
- Geske, J.B.; Bos, J.M.; Gersh, B.J.; Ommen, S.R.; Eidem, B.W.; Ackerman, M.J. Deformation patterns in genotyped patients with hypertrophic cardiomyopathy. Eur. Heart J.-Cardiovasc. Imaging 2013, 15, 456–465. [Google Scholar] [CrossRef] [Green Version]
Figure 1.
Echocardiographic analysis of the left ventricle. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy, compared between MYBPC3 (dark blue) and MYH7 (light blue) mutation carriers. (a) Left ventricular strain analysis user—(LVGLS) (p = 0.807) and automatically (LVGLS auto) (p = 0.892) generated; (b) Ejection fraction of the left ventricle (%) measured biplane (Simpson) (p = 0.338) and triplane (p = 0.410) in %; (c) enddiastolic basal diameter of the left ventricle (LVd) (p = 0.693) and maximal enddiastolic thickness of the interventricular septum (IVSd) (p = 0.897).
Figure 1.
Echocardiographic analysis of the left ventricle. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy, compared between MYBPC3 (dark blue) and MYH7 (light blue) mutation carriers. (a) Left ventricular strain analysis user—(LVGLS) (p = 0.807) and automatically (LVGLS auto) (p = 0.892) generated; (b) Ejection fraction of the left ventricle (%) measured biplane (Simpson) (p = 0.338) and triplane (p = 0.410) in %; (c) enddiastolic basal diameter of the left ventricle (LVd) (p = 0.693) and maximal enddiastolic thickness of the interventricular septum (IVSd) (p = 0.897).
Figure 2.
Echocardiographic analysis of the diastolic function and the atrial volume. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy compared between MYBPC3 (dark orange) and MYH7 (light orange) mutation carriers. (a) ratio of early transmitral velocity to average velocity of the transmitral annulus (E/e′) (p = 0.630) and maximal tricuspid regurgitation velocity (TRVmax) (p = 0.390); (b) left atrial volume index (LAVi) (p = 0.637) and right atrial volume index (RAVi) (p = 0.443).
Figure 2.
Echocardiographic analysis of the diastolic function and the atrial volume. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy compared between MYBPC3 (dark orange) and MYH7 (light orange) mutation carriers. (a) ratio of early transmitral velocity to average velocity of the transmitral annulus (E/e′) (p = 0.630) and maximal tricuspid regurgitation velocity (TRVmax) (p = 0.390); (b) left atrial volume index (LAVi) (p = 0.637) and right atrial volume index (RAVi) (p = 0.443).
Figure 3.
Echocardiographic analysis of the right ventricle. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy and compared between MYBPC3 (dark green) and MYH7 (light green) mutation carriers. (a) Right ventricular strain analysis (RV4CLS) (p = 0.285) and strain analysis of the right free wall (RVFWLS) (p = 0.643); (b) right ventricular fractional area change (RVFAC) (p = 0.007), tricuspid annular plane systolic excursion (TAPSE) (p = 0.798); (c) enddiastolic basal diameter of the right ventricle (RVd) (p = 0.551) and enddiastolic thickness of the right ventricular free wall (RVWT) (p = 0.917).
Figure 3.
Echocardiographic analysis of the right ventricle. Estimated marginal means and standard error adjusted for age, sex and septum reduction therapy and compared between MYBPC3 (dark green) and MYH7 (light green) mutation carriers. (a) Right ventricular strain analysis (RV4CLS) (p = 0.285) and strain analysis of the right free wall (RVFWLS) (p = 0.643); (b) right ventricular fractional area change (RVFAC) (p = 0.007), tricuspid annular plane systolic excursion (TAPSE) (p = 0.798); (c) enddiastolic basal diameter of the right ventricle (RVd) (p = 0.551) and enddiastolic thickness of the right ventricular free wall (RVWT) (p = 0.917).
Table 1.
Echocardiography derived parameters.
| Chamber | Parameter |
|---|---|
| Left ventricle | LVEF, Simpson’s biplane (%) LVEF, triplane, 2dCPA (%) |
| Transmitral E velocity (cm/s) | |
| Septal annular e′ velocity (cm/s) | |
| Lateral annular e′ velocity (cm/s) | |
| LV E/e′ (average) ratio LV GLS, auto-strain (%) LV GLS, 2dCPA (%) | |
| Left atrium | LAVi (mL/m2) |
| Right ventricle | RV basal ED diameter (mm) |
| RV wall thickness (mm) | |
| TAPSE (mm) TRVmax (m/s) | |
| Fractional area change (%) RVLS 6 segments, 2dCPA (%) RVLS free wall, 2dCPA (%) | |
| Right atrium | RAVi (mL/m2) |
Abbreviations: LV, left ventricular; EF, ejection fraction; 2dCPA, two-dimensional cardiac performance analysis; E, transmitral early diastolic velocity; e′, mitral annular early diastolic velocity; LAVi, left atrial volume index; GLS, global longitudinal strain; RV, right ventricular; ED, end-diastolic; TAPSE, tricuspid annular plane systolic excursion; TRVmax, maximal tricuspid regurgitation velocity; RLVS, right ventricular longitudinal strain; RAVi, right atrial volume index.
Table 2.
Clinical characteristics and medical history.
| Whole Cohort (n = 57) | MYBPC3 (n = 39) | MYH7 (n = 18) | t-Test/Pearson Chi2-Test | |
|---|---|---|---|---|
| Characteristics | n (%) or Mean ± SD or Median (IQR) | n (%) or Mean ± SD or Median (IQR) | n (%) or Mean ± SD or Median (IQR) | p Value |
| Female | 28 (49.1) | 16 (41.0) | 12 (66.7) | p = 0.072 |
| Age (years) | 49.07 ± 15.24 | 51.82 ± 14.40 | 41.44 ± 13.95 | p = 0.013 |
| Age at first diagnosis (years) 1 | 40.78 ± 15.55 | 41.80 ± 14.61 | 36.4 ±16.91 | p = 0.259 |
| BMI (kg/m2) 2 | 27.52 ± 5.90 | 26.55 ± 4.47 | 29.59 ± 7.91 | p = 0.143 |
| RR systolic (mmHg) 2 | 134.73 ± 18.31 | 135.88 ± 19.13 | 132.33 ± 16.71 | p = 0.505 |
| RR diastolic (mmHg) 2 | 80.32 ± 10.04 | 79.71 ± 10.18 | 81.61 ± 9.91 | p = 0.513 |
| Heartrate (beats/min) | 67.39 ± 10.20 | 68.44 ± 10.04 | 65.11 ± 10.44 | p = 0.256 |
| NYHA > II | 19 (33.3) | 15 (38.5) | 4 (22.3) | p = 0.227 |
| LVOT obstruction | 22 (38.6) | 16 (41.0) | 6 (33.3) | p = 0.579 |
| Loop diuretics | 8 (14.0) | 8 (20.5) | 0 | p = 0.038 |
| MRA | 5 (8.8) | 4 (10.3) | 1 (5.6) | p = 0.560 |
| Verapamil | 5 (8.8) | 4 (10.3) | 1 (5.6) | p = 0.560 |
| Amiodarone | 3 (5.3) | 2 (5.1) | 1 (5.6) | p = 0.946 |
| ACEI/ARB/ARNI | 12 (21.2) | 11 (28.2) | 1 (5.6) | p = 0.051 |
| NTproBNP (pg/mL) | 536 (193, 1470) | 817 (197, 2802) | 390 (164, 789) | p = 0.158 |
| eGFR (ml/min/1.73 m) | 86.89 ± 27.07 | 80.55 ± 22.4 | 100.62 ± 31.62 | p = 0.008 |
| History | ||||
| Surgical myectomy | 3 (5.3) | 1 (2.6) | 2 (11.1) | p = 0.179 |
| PTSMA | 9 (15.8) | 7 (17.9) | 2 (11.1) | p = 0.510 |
| Mitral valve replacement/repair | 0 | 0 | 0 | |
| Survived sudden cardiac death | 7 (12.3) | 6 (15.4) | 1 (5.6) * | p = 0.293 |
| Hospitalization for WHF | 8 (14.0) | 7 (17.9) | 1 (5.6) | p = 0.211 |
| Arterial hypertension | 23 (40.4) | 17 (43.6) | 6 (33.3) | p = 0.463 |
| Stroke | 4 (7.0) | 4 (10.3) | 0 | p = 0.132 |
| PE | 3 (5.3) | 2 (5.1) | 1 (5.6) | p = 0.946 |
| AF | 13 (22.8) | 12 (30.8) | 1 (5.6) | p = 0.035 |
| permanent | 4 (30.8 **) | 4 (33.3 **) | 0 | p = 0.159 |
| paroxysmal | 8 (61.5 **) | 8 (66.7 **) | 1 (100 **) | p = 0.150 |
| ECG | ||||
| Sinus rhythm | 48 (84.3) | 30 (77) | 18 (100) | p = 0.026 |
| Ventricular stimulated rhythm | 5 (8.8) | 5 (12.8) | 0 | p = 0.112 |
| Atrial fibrillation | 4 (7.0) | 4 (10.3) | 0 | p = 0.159 |
| QRS duration (ms) | 111.43 ± 33.67 | 113.8 5 ± 37.72 | 104.67 ± 21.65 | p = 0.251 |
| LBBB | 19 (33.3) | 11 (28.2) | 8 (44.4) | p = 0.227 |
| RBBB | 11 (19.3) | 8 (20.5) | 3 (16.7) | p = 0.732 |
| Devices | ||||
| Pacemaker | 15 (26.3) | 15 (38.5) | 0 | p = 0.002 |
| CRT | 1 (1.8) | 1 (2.6) | 0 | p = 0.493 |
| ICD | 15 (26.3) | 15 (38.5) | 0 * | p = 0.002 |
| ICD shock | 4 (26.7 **) | 4 (26.7 **) | ||
| Primary prevention | 9 (60.0 **) | 9 (60.0 **) | ||
| Secondary prevention | 6 (40.0 **) | 6 (40.0 **) |
1 MYBPC3 (n = 35) MYH7 (n = 15). 2 MYBPC3 (n = 38). * patient refused ICD therapy. ** Relative percentage. Bold, statistically significant. Abbreviations: SD, standard deviation, IQR, interquartile range; BMI, body mass index; RR, blood pressure; NYHA, New York Heart Association; LVOT, left ventricular outflow tract; MRA, mineral corticoid receptor antagonist; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilyin inhibitor; NTproBNP, N-terminal pro-brain natriuretic peptide; eGFR, estimated glomerular filtration rate; PTSMA, percutaneous transluminal septal myocardial ablation; WHF, worsening heart failure; PE, pulmonary embolism; AF, atrial fibrillation; LBBB, left bundle branch block; RBBB, right bundle branch block; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator.
Table 3.
Echocardiographic parameters compared between MYBPC3 and MYH7 mutation carriers.
| MYBPC3 (n = 39) | MYH7 (n = 18) | t-Test | ANCOVA | |||
|---|---|---|---|---|---|---|
| Not Adjusted | Adjusted | Not Adjusted | Adjusted | |||
| Mean ± SD or Median (IQR) | Mean ± SE | Mean ± SD or Median (IQR) | Mean ± SE | p Value | p Value | |
| Sinus rhythm during TTE n (%) | 30 (77) | 18 (100) | ||||
| heart rate during TTE (beats/min) | 68.44 ± 10.04 | 68.9 ± 1.7 | 65.11 ± 10.44 | 64.0 ± 2.6 | p = 0.256 | p = 0.139 |
| LV average loops | 2 ± 0 | 2 ± 0 | ||||
| RV average loops | 2.53 ± 0.6 | 2.47 ± 0.7 | ||||
| LV | ||||||
| LVGLS auto 1 | −16.7 ± 4.1 | −17.2 ± 0.6 | −18.3 ± 2.6 | −17.3 ± 0.9 | p = 0.138 | p = 0.892 |
| LVGLS 2dCPA | −16.5 ± 4.0 | −16.9 ± 0.6 | −18.3 ± 2.8 | −17.3 ± 0.9 | p = 0.088 | p = 0.807 |
| LVEF Simpson biplane (%) 2 | 52.9 ± 8.0 | 53.03 ± 1.2 | 56.3 ± 4.8 | 55.4 ± 1.8 | p = 0.100 | p = 0.338 |
| LVEF triplane (%) | 51.1 ± 8.6 | 51.6 ± 1.3 | 54.7 ± 4.8 | 53.5 ± 1.9 | p = 0.105 | p = 0.410 |
| E/e′ average (ratio) 3 | 11.4 ± 5.8 | 11.0 ± 0.9 | 11.1 ± 4.6 | 11.9 ± 1.4 | p = 0.652 | p = 0.630 |
| E (cm/s) 3 | 83.0 ± 27.1 | 84.3 ± 4.6 | 79.4 ± 22.6 | 76.7 ± 7.1 | p = 0.647 | p = 0.397 |
| e′ average (cm/s) 3 | 8.1 ± 2.7 | 8.5 ± 0.4 | 7.7 ± 2.4 | 6.8 ± 0.6 | p = 0.892 | p = 0.026 |
| IVSd maximal (mm) | 20.8 ± 4.6 | 20.3 ± 0.8 | 19.2 ± 4.8 | 20.1 ± 1.1 | p = 0.226 | p = 0.897 |
| IVSd basal (mm) | 15.2 ± 3.8 | 14.9 ± 0.6 | 13.5 ± 3.8 | 14.3 ± 0.9 | p = 0.125 | p = 0.626 |
| IVSd midventricular (mm) | 20.7 ± 4.6 | 20.2 ± 0.8 | 19.1 ± 4.7 | 20.1 ± 1.1 | p = 0.233 | p = 0.911 |
| IVSd apical (mm) | 14.4 ± 4.6 | 14.1 ± 0.7 | 13.7 ± 4.3 | 14.3 ± 1.1 | p = 0.593 | p = 0.868 |
| LVEDd (cm) | 3.03 ± 0.54 | 2.98 ± 0.1 | 2.94 ± 0.36 | 3.04 ± 0.11 | p = 0.527 | p = 0.693 |
| LAVi MOD (mL/m2) 4 | 50.2 (37.8, 68.8) | 54.3 ± 4.7 | 42.5 (33.5, 49.9) | 50.1 ± 7.2 | p = 0.097 | p = 0.637 |
| RV | ||||||
| RVLS 6 segments 2dCPA 5 | −24.1 ± 6.3 | −24.3 ± 1.0 | −26.9 ± 3.8 | −26.3 ± 1.5 | p = 0.062 | p = 0.285 |
| RVLS free wall 2dCPA 5 | −29.1 ± 7.4 | −29.4 ± 1.2 | −30.9 ± 4.2 | −30.4 ± 1.8 | p = 0.395 | p = 0.643 |
| RVFAC (%) 2 | 43.5 ± 10.9 | 43.7 ± 1.7 | 52.8 ± 7.4 | 52.4 ± 2.5 | p = 0.002 | p = 0.007 |
| TRVmax (m/s) 6 | 2.6 ± 0.4 | 2.6 ± 0.1 | 2.5 ± 0.2 | 2.5 ± 0.1 | p = 0.206 | p = 0.390 |
| TAPSE (mm) 7 | 21.9 ± 4.5 | 22.1 ± 0.8 | 22.2 ± 5.0 | 21.7 ± 1.3 | p = 0.823 | p = 0.798 |
| RVEDd basal (mm) 2 | 38.4 ± 7.1 | 37.5 ± 1.2 | 34.3 ± 8.2 | 36.2 ± 1.8 | p = 0.059 | p = 0.551 |
| RVWT (mm) 8 | 7.2 ± 1.7 | 7.2 ± 0.3 | 7.2 ± 2.0 | 7.2 ± 0.5 | p = 0.950 | p = 0.917 |
| RA Area (cm2) 9 | 18.5 ± 1.0 | 18.3 ± 1.0 | 16.6 ± 1.6 | 17.3 ± 1.6 | p = 0.045 | p = 0.619 |
| RAVi (mL/m2) 2,9 | 31.4 ± 19.1 | 29.1 ± 2.5 | 20.3 ± 7.4 | 25.3 ± 3.9 | p = 0.003 | p = 0.443 |
1 MYBPC3 (n = 34), MYH7 (n = 17). 2 MYBPC3 (n = 38). 3 MYBPC3 (n = 33), MYH7 (n = 15). 4 MYBPC3 (n = 35) MYH7 (n = 16). 5 MYBPC3 (n = 32), MYH7 (n = 15). 6 MYBPC3 (n = 25), MYH7 (n = 7). 7 MYBPC3 (n = 35), MYH7 (n = 14). 8 MYBPC3 (n = 31), MYH7 (n = 13). 9 MYH7 (n = 17). Bold, statistically significant. Abbreviatons: SD, standard deviation; IQR, interquartile range; SE, standard error; ANCOVA, analysis of covariance; TTE, transthoracic echocardiography; LV, left ventricule/ventricular; RV, right ventricle/ventricular; GLS, global longitudinal strain; auto, automatically generated; 2dCPA, 2D cardiac performance analysis; EF, ejection fraction; E, transmitral early diastolic velocity; e′, mitral annular early diastolic velocity; IVS, interventricular septum; d, diameter; ED, end-diastolic; LAVi, left atrial volume index; MOD, method of discs; LS, longitudinal strain; FAC, fractional area change; TRVmax, maximal tricuspid regurgitation velocity; TAPSE, tricuspid annular plane systolic excursion; WT, wall thickness; RAVi, right atrial volume index.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Höller, V.; Seebacher, H.; Zach, D.; Schwegel, N.; Ablasser, K.; Kolesnik, E.; Gollmer, J.; Waltl, G.; Rainer, P.P.; Verheyen, S.; et al. Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy—The Graz Hypertrophic Cardiomyopathy Registry. Genes 2021, 12, 1469. https://doi.org/10.3390/genes12101469
AMA Style
Höller V, Seebacher H, Zach D, Schwegel N, Ablasser K, Kolesnik E, Gollmer J, Waltl G, Rainer PP, Verheyen S, et al. Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy—The Graz Hypertrophic Cardiomyopathy Registry. Genes. 2021; 12(10):1469. https://doi.org/10.3390/genes12101469
Chicago/Turabian StyleHöller, Viktoria, Heidelis Seebacher, David Zach, Nora Schwegel, Klemens Ablasser, Ewald Kolesnik, Johannes Gollmer, Gert Waltl, Peter P. Rainer, Sarah Verheyen, and et al. 2021. "Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy—The Graz Hypertrophic Cardiomyopathy Registry" Genes 12, no. 10: 1469. https://doi.org/10.3390/genes12101469
APA StyleHöller, V., Seebacher, H., Zach, D., Schwegel, N., Ablasser, K., Kolesnik, E., Gollmer, J., Waltl, G., Rainer, P. P., Verheyen, S., Zirlik, A., & Verheyen, N. (2021). Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy—The Graz Hypertrophic Cardiomyopathy Registry. Genes, 12(10), 1469. https://doi.org/10.3390/genes12101469
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
