Purpose Previous studies suggest that anterior mitral valve leaflet (AMVL) elongation is a primary phenotypic feature in hypertrophic cardiomyopathy (HCM). Our aim was to assess AMVL length in individuals with HCM gene mutations and in healthy controls and to identify predictors of the development of HCM during follow-up. Methods A total of 133 HCM mutation carriers and 135 controls underwent cardiac examination including electro- and echocardiography. AMVL length was measured in the parasternal long axis and apical three chamber view during diastole. Univariate and multivariable cox proportional hazard regression analyses were performed to identify predictors of HCM. Results There were no significant differences between HCM mutation carriers and controls regarding age and sex. In the parasternal long axis view, AMVL length was similar in mutation carriers and controls (24 ± 4 vs 24 ± 4 mm, p = 0.8). In the apical three chamber view, AMVL were shorter in mutation carriers (29 ± 4 vs 30 ± 4 mm, p = 0.02). When averaged for both views, AMVL length was similar in mutation carriers and controls (27 ± 3 vs 27 ± 3 mm, p = 0.2). During 5.8 ± 3.0 years follow-up, 13 (14%) HCM mutation carriers developed HCM. Pathological Q wave (hazard ratio 9.89, p = 0.004), E/e′ ratio (hazard ratio 2.52, p = 0.001), and maximal wall thickness (hazard ratio 2.15, p = 0.001) were independent predictors of HCM. AMVL length was not predictive of the development of HCM. Conclusions AMVL length is similar in HCM mutation carriers and controls. AMVL length is not predictive of the develop- ment of HCM, in contrast to pathological Q wave, E/e′ ratio, and maximal wall thickness. Keywords Echocardiography · Genetics · Hypertrophic cardiomyopathy · Mitral valve · Screening SOMMARIO Obiettivi Studi precedenti suggeriscono che l’allungamento della cuspide anteriore della valvola mitrale (LAVM) è una caratteristica fenotipica primaria nella cardiomiopatia ipertrofica (HCM). Il nostro obiettivo era quello di valutare la lung - hezza del LAVM in individui con mutazioni del gene HCM e nei controlli sani e di identificare i predittori dello sviluppo di HCM durante il follow-up. Metodi Un totale di 133 portatori di mutazione HCM e 135 controlli sono stati sottoposti ad un esame cardiologico che comprendeva un elettrocardiogramma ed ecocardiografia. La lunghezza del LAVM è stata misurata durante la fase diastolica in proiezione parasternale asse longitudinale ed in proiezione 3 camere apicali. Le analisi di regressione del rischio propor- zionale coassiale univariata e multivariata sono state eseguite per identificare I predittori di HCM. Risultati Non sono risultate differenze significative tra portatori di mutazione HCM e controlli per quanto riguarda età e sesso. Nella proiezione parasternale asse lungo, la lunghezza del LAVM era simile nei portatori di mutazione e controlli (24 ± 4 vs 24 ± 4 mm, p = 0.8). Nella proiezione 3 camere apicale, i valori del LAVM erano minori nei portatori di mutazione (29 ± 4 vs 30 ± 4 mm, p = 0.02). Eseguendo la media dei valori per entrambe le proiezioni, la lunghezza del LAVM era simile nei portatori di mutazione e nei controlli (27 ± 3 vs 27 ± 3 mm, p = 0.2). Durante un periodo di follow-up di 5.8 ± 3.0 anni, 13 (14%) dei portatori della mutazione HCM hanno sviluppato HCM. L’onda Q patologica (hazard ratio 9.89, p = 0,004), il Extended author information available on the last page of the article Vol.:(0123456789) 1 3 218 Journal of Ultrasound (2018) 21:217–224 rapporto E/e′ (hazard ratio 2.52, p = 0.001) e lo spessore massimale della parete (hazard ratio 2.15, p = 0.001) sono risultati predittori indipendenti di HCM. La lunghezza del LAVM non era predittiva di sviluppo di HCM. Conclusioni La lunghezza del LAVM è simile nei portatori della mutazione HCM e nei controlli. La lunghezza del LAVM non è risultata predittiva dello sviluppo di HCM, a differenza dell’onda Q patologica, del rapporto E/e’, e dello spessore massimale della parete. breast implants . The study conforms to the principles Introduction of the Declaration of Helsinki. All patients gave informed consent for inclusion in the registry and local institutional Hypertrophic cardiomyopathy (HCM) is a genetic car- review board approval was obtained. diac disease with an estimated prevalence of 1:500–1:200 [1–3]. The diagnosis is based on the presence of a maximal wall thickness ≥ 15 mm in index patients and ≥ 13 mm in Clinical evaluation relatives, that is not solely explained by abnormal loading conditions . A pathogenic HCM mutation is identified Clinical evaluation included medical history, physical exam- in 40–60% of patients with HCM [2, 4]. Presymptomatic ination, ECG, and transthoracic echocardiography. Standard genetic testing of relatives has led to the identification of 12-lead ECG was performed in the supine position during HCM gene mutation carriers who do not fulfill the echocar - quiet respiration. LV hypertrophy was evaluated with the diographic criterion of HCM . HCM mutation carriers Romhilt–Estes criteria. Pathological Q waves were defined are at risk of developing HCM . Conflicting data exists as duration > 40 ms or depth > 30% R wave in ≥ 2 leads. T on whether the anterior mitral valve leaflets (AMVL) are wave inversion was defined as ≥ 3 mm in ≥ 2 leads. Echo- elongated in mutation carriers and whether AMVL elon- cardiographic studies were analyzed according to the guide- gation is a predictor of the development of HCM during lines [15, 16]. Maximal wall thickness, left atrial size, leaflet follow-up [6–11]. The aim of this study was to assess AMVL and chordal systolic anterior motion of the mitral valve, and length in HCM mutation carriers and healthy controls and resting LV outflow tract peak velocity were assessed. LV to determine the prognostic significance of AMVL length in outflow tract gradient was calculated with the Bernoulli HCM mutation carriers for the development of HCM during equation. LV systolic function was categorized as: good follow-up. (LV ejection fraction > 51%), mildly reduced (LV ejection fraction 41–51%), moderately reduced (LV ejection fraction 30–40%), and poor (LV ejection fraction < 30%) . LV diastolic function was defined as normal, abnormal relaxa- Methods tion, pseudonormal or restrictive filling, based on Doppler mitral inflow pattern parameters including early (E) and Study design and population late (A) LV filling velocities, E/A ratio, and tissue Doppler imaging-derived septal early diastolic velocities (e′) . This single-center retrospective case–control and cohort HCM during follow-up was defined as a maximal wall thick - study included 133 HCM mutation carriers without clinical ness ≥ 13 mm according to the guidelines . expression of HCM who were clinically evaluated at our car- dio-genetic outpatient clinic between the years 2004–2017. AMVL measurements Genetic assessment and the family screening strategy at our center have been described previously [12, 13]. For com- AMVL length was measured in the parasternal long axis parison, 135 healthy controls underwent cardiac evaluation (PLAX) view and in the apical three chamber (A3C) view, . Controls were recruited via an advertisement. Inclu- during diastole and with the leaflet maximally extended. sion criteria were normal physical examination, normal elec- In the PLAX view, leaflet length was defined as the dis - trocardiography (ECG), and left ventricular (LV) ejection tance from the tip of the leaflet to the junction between the fraction > 51%; exclusion criteria were prior cardiovascular anterior leaflet and the posterior aortic wall (hinge point), disease or risk factors consisting of hypertension, diabetes according to Klues et al. . In the A3C view, leae fl t length mellitus, and hypercholesterolemia, systemic disease, medi- was defined as the distance from the tip of the leaflet to cation known to influence cardiac function including thyroid the insertion of the noncoronary aortic leaflet, according to medication (with the exception of asthma inhalers), profes- Alhaj et al. . Examples of AMVL measurements in both sional athletes, body mass index > 40 and women with views are shown in Fig. 1. All AMVL measurements were 1 3 Journal of Ultrasound (2018) 21:217–224 219 Fig. 1 Example of anterior mitral valve leaflet length (AMVL) meas- AMVL measured 26 mm, and in the apical three chamber view, b the urements in a hypertrophic cardiomyopathy gene mutation carrier AMVL measured 26 mm without hypertrophic changes. In the parasternal long-axis view, a the performed by one reader. For intraobserver variability, one used. This is an alternative method to determine the num- reader independently measured 40 AMVLs in the PLAX ber of variables allowed for inclusion in the multivariable view and 40 AMVLs in the A3C view in an identical fashion analysis . on two occasions. For interobserver variability, two readers independently measured 20 AMVLs in the PLAX view and 20 AMVLs in the A3C view. Results Statistical methods Clinical evaluation The statistical analysis was performed using SPSS 21 (IBM, HCM gene mutation carriers represented mutations in 10 Armonk, NY). Normally distributed continuous data are different genes. The MYBPC3 gene was most frequently expressed as mean ± standard deviation and non-normally affected (77%), followed by the MYH7 gene (11%). Other distributed data as median followed by interquartile range. genes affected were TNNT2 (3%), MYL2 (2%), FHL1 (2%), For comparing categorical variables Pearson’s Chi-square ALPK3 (2%) MIB1 (0.75%), TNNI3 (0.75%), TPM1 (0.75%), test was used. For comparing continuous variables t test was and MYL3 (0.75%). Clinical and echocardiographic char- used, and Mann–Whitney U in case of non-normally distrib- acteristics in mutation carriers and controls are presented uted data. All analyses were two-sided; p values < 0.05 were in Table 1. Mutation carriers and controls had similar considered significant. Inter-observer and intra-observer age, gender, and body surface area. Compared to controls, agreement was defined as the mean of the difference between more mutation carriers had pathological Q waves (4 vs two measurements ± standard deviation. Univariate and mul- 0%, p = 0.02), and mutation carriers had a higher E/e′ ratio tivariable cox proportional hazard regression was performed (8.2 ± 1.9 vs 7.7 ± 1.9, p = 0.03), and a higher maximal wall to determine hazard ratios (HR) and 95% confidence inter - thickness (8.9 ± 1.9 vs 8.0 ± 1.8 mm, p = 0.001). vals (CI). After screening for multicollinearity, the univari- ate significant variables with the highest HR were entered AMVL measurements into the multivariable regression model. To calculate the allowed number of variables for inclusion in the multivari- Beeswarm plots of AMVL measurements in the PLAX and able analysis, the square root of the number of events was the A3C view are presented in Fig. 2. In the PLAX view, 1 3 220 Journal of Ultrasound (2018) 21:217–224 Table 1 Clinical and Variable Mutation carrier Control (n = 135) p value echocardiographic (n = 133) characteristics of the study population Age (year) 41 ± 14 44 ± 14 0.11 Female gender n (%) 85 (64) 73 (54) 0.18 Body surface area (m ) 1.9 ± 0.2 1.9 ± 0.2 0.86 Electrocardiography Romhilt–Estes ≥ 4 n (%) 10 (8) 4 (3) 0.09 T wave inversion n (%) 1 (1) 0 (0) 0.31 Pathological Q wave n (%) 5 (4) 0 (0) 0.02 Echocardiography Maximal wall thickness (mm) 8.9 ± 2.0 8.0 ± 1.8 <0.001 Left atrial size (mm) 34 ± 5 34 ± 4 0.24 LVOT gradient ≥ 30 mmHg n (%) 0 (0) 0 (0) 0.50 AMVL, PLAX (mm) 24 ± 4 24 ± 4 0.85 AMVL, A3C (mm) 29 ± 4 30 ± 4 0.02 AMVL, averaged (mm) 27 ± 3 27 ± 3 0.17 Chordal systolic anterior motion n (%) 5 (4) 1 (1) 0.09 Leaflet systolic anterior motion n (%) 0 (0) 0 (0) 0.50 E/A ratio 1.4 ± 0.5 1.6 ± 0.7 0.03 E/e’ ratio 8.2 ± 1.9 7.7 ± 1.9 0.03 Septal e’ (cm/s) 9.5 ± 2.5 9.6 ± 2.6 0.61 Diastolic function Normal n (%) 105 (83) 111 (85) 0.66 Abnormal relaxation n (%) 10 (8) 7 (5) 0.39 Pseudonormal filling n (%) 11 (9) 13 (10) 0.76 Restrictive filling n (%) 0 (0) 0 (0) 0.50 Systolic function Good n (%) 132 (99) 135 (100) 0.31 Mildly reduced n (%) 1 (1) 0 (0) 0.31 Moderately reduced n (%) 0 (0) 0 (0) 0.50 Poor n (%) 0 (0) 0 (0) 0.50 Data are expressed as mean ± standard deviation or as absolute and (%) AMVL anterior mitral valve leaflet, A3C apical three chamber view, LVOT left ventricular outflow tract, PLAX parasternal long-axis view at rest Fig. 2 Beeswarm plot of anterior mitral valve leaflet (AMVL) length measurements in hypertrophic cardiomyopathy gene mutation carriers without hypertrophic changes versus healthy controls, assessed with transthoracic echocardiography in the a parasternal long-axis view and b apical three chamber view AMVL length did not differ between mutation carriers and 30 ± 4 mm, p = 0.02). When averaged for both views, AMVL controls (24 ± 4 vs 24 ± 4 mm, p = 0.8). In the A3C view, length was similar in mutation carriers and controls (27 ± 3 AMVL were shorter in the mutation carriers (29 ± 4 vs vs 27 ± 3 mm, p = 0.2). Overall, AMVL were significantly 1 3 Journal of Ultrasound (2018) 21:217–224 221 longer in the A3C view than in the PLAX view (30 ± 4 vs of the development of HCM in the PLAX view (HR 1.03, 24 ± 4 mm, p < 0.001). 95% CI 0.87–1.22, p = 0.72) or in the A3C view (HR 0.99, 95% CI 0.86–1.15, p = 0.92). Multivariable cox regression Intra‑observer and inter‑observer agreement analysis which included three variables demonstrates that pathological Q wave (adjusted HR 9.89, 95% CI 2.09–46.95, In the PLAX view, the inter-observer agreement was p = 0.004), E/e′ ratio (adjusted HR 2.52, 95% CI 1.48–4.29, − 2.7 ± 2.6 mm and the intra-observer agreement was p = 0.001), and maximal wall thickness (adjusted HR 2.15, − 1.0 ± 3.5 mm. In the A3C view, the inter-observer agree- 95% CI 1.36–3.42, p = 0.001) all were independent predic- ment was 2.0 ± 2.5 mm and the intra-observer agreement tors of HCM during follow-up. was 0.5 ± 2.6 mm. Follow‑up Discussion During 5.8 ± 3.0 years follow-up, 13 (14%) mutation car- During HCM family screening, individuals who carry a riers developed HCM. Mean age at HCM diagnosis was HCM gene mutation may not fulfil the echocardiographic 52 ± 17 years. In these 13 mutation carriers, maximal wall diagnostic criterion of HCM . Because of the age-related thickness increased from a median 10 (interquartile range 8, penetrance of HCM, long-term clinical follow-up includ- 11) mm to 13 (interquartile range 13, 14) mm, with a mean ing ECG and echocardiography is recommended [2, 3]. rate of 0.7 ± 0.3 mm/year. Table 2 presents the baseline char- Currently, it is unclear which HCM mutation carriers will acteristics in those who developed HCM during follow-up develop HCM [2, 11]. We aimed to assess AMVL length in and those who did not. Univariate significant predictors of mutation carriers and controls, and determine the prognostic the development of HCM were pathological Q wave (HR value of AMVL length for the development of HCM during 9.74, 95% CI 2.53–37.46, p = 0.001), maximal wall thick- follow-up. Our main findings are: (1) AMVL length is simi- ness (HR 1.64, 95% CI 1.12–2.39, p = 0.01), E/e′ ratio (HR lar in mutation carriers and controls, (2) AMVL length is not 1.63, 95% CI 1.20–2.23, p = 0.002), left atrial size (HR predictive of the development of HCM, and (3) pathological 1.16, 95% CI 1.03–1.31, p = 0.01), and age (HR 1.06, 95% Q wave, E/e′ ratio, and maximal wall thickness are independ- CI 1.02–1.11, p = 0.01). AMVL length was not predictive ent predictors of the development of HCM. AMVL elongation is not a primary phenotypic Table 2 Baseline characteristics of HCM gene mutation carriers who feature of HCM did and did not develop hypertrophic cardiomyopathy during follow- up In patients with HCM, AMVL elongation has been dem- Variable Developed HCM onstrated pathologically, on echocardiography, and on car- Yes (n = 13) No (n = 77) p value diovascular magnetic resonance imaging [10, 18, 21–23]. Among other factors, AMVL elongation contributes to Age (years) 47 ± 19 39 ± 13 0.05 systolic anterior motion of the mitral valve and LV outflow Male gender n (%) 8 (62) 25 (33) 0.04 tract obstruction [23–25]. The etiology of AMVL elonga- Romhilt–Estes ≥ 4 n (%) 1 (8) 5 (7) 0.87 tion in patients with HCM is unclear. Both the pathological T wave inversion n (%) 1 (8) 0 (0) 0.01 study of Klues et al. and the in vivo study of Kim et al. Pathological Q n (%) 3 (23) 2 (3) 0.003 found that AMVL elongation is not secondary to LV outflow Left atrial size (mm) 39 ± 5 33 ± 5 <0.001 tract obstruction or systolic anterior motion of the mitral Maximal wall thickness (mm) 10 ± 2 9 ± 2 0.02 valve, since it also occurs in patients without LV outflow AMVL, PLAX (mm) 25 ± 5 24 ± 3 0.47 tract obstruction or systolic anterior motion [19, 21, 22]. AMVL, A3C (mm) 29 ± 5 29 ± 4 0.90 Therefore, it was suggested that AMVL elongation is a pri- Chordal systolic anterior motion 1 (8) 3 (4) 0.54 mary phenotypic expression of HCM. Several studies have n (%) indeed reported AMVL elongation in mutation carriers as E/e’ ratio 9.3 ± 1.8 8.1 ± 1.7 0.03 measured by magnetic resonance imaging [6, 7, 10], and Septal e’ (cm/s) 8.5 ± 2.7 9.5 ± 2.6 0.20 echocardiography . The current study contradicts these Abnormal diastolic function n 4 (31) 11 (16) 0.21 (%) findings. In line with our findings, a recent magnetic res- onance imaging study similarly reported no difference in Data are expressed as mean ± standard deviation or as absolute and AMVL length between mutation carriers and controls . (%) The discrepancy between the studies may be related to the AMVL anterior mitral valve leaflet, A3C apical three chamber view, small number of participants, different imaging modalities HCM hypertrophic cardiomyopathy, PLAX parasternal long axis view 1 3 222 Journal of Ultrasound (2018) 21:217–224 used, different distribution of genetic mutations, or different technical difficulty of distinguishing the mitral leaflet from methodologies used for AMVL measurements. the chordae tendineae, and by the frame-to-frame variabil- For several reasons, we believe it is unlikely that HCM ity in AMVL length caused by AMVL movement during gene mutations cause AMVL elongation. First, there are no diastole and respiration. Intra-observer agreement was best sarcomeric proteins in the mitral valve leaflet . Second, for the A3C view, which was unexpected because in the a HCM animal model including heterozygous cardiac myo- PLAX view the distance to the transducer is shorter. It may sin-binding protein C targeted knock-out mice embryos did be explained by the landmarks that were used; in the A3C not show mitral leaflet elongation . Third, Captur et al. view the insertion of the noncoronary aortic leaflet is more observed AMVL elongation in genotype-negative patients easily identifiable in comparison to the hinge point in the with HCM . And finally, most morphological studies PLAX view. Finally, AMVL were significantly longer in the demonstrate that mitral leaflets are intrinsically normal [ 21, A3C view than in the PLAX view; the measurement in the 27]. Other potential etiologies of AMVL elongation are A3C view included the intervalvular fibrosa. being investigated, such as the paracrine effects from the abnormal LV wall which influences valvulogenesis, or the Limitations abnormal differentiation of pluripotent epicardial-derived cells into fibroblast-cells with increased synthesis of peri- This study has several limitations. First, although the study ostin which might drive leaflet elongation . population is large compared to previous studies, a higher sample size would reduce the risk of sampling error. Second, Predicting the development of HCM the proportion of HCM gene mutation carriers that devel- oped HCM during follow-up was limited. The current study demonstrates that AMVL length had no predictive value for the development of HCM. Hence, AMVL length cannot be used as a preclinical marker of the Conclusions development of HCM. Similar observations were made in a prior smaller study by Ho et al. . Pathological Q wave AMVL length is similar in HCM mutation carriers and had a high predictive value for the development of HCM. healthy controls. AMVL length is not a predictor of the Indeed, prior investigation of ECGs in genotyped HCM development of HCM during follow-up, in contrast to patho- populations demonstrated that Q waves and repolarization logical Q wave, E/e′ ratio, and maximal wall thickness. abnormalities are the most distinguishing ECG manifesta- tions of sarcomere mutations . However, the clinical util- Compliance with ethical standards ity of Q waves is probably limited because of the low nega- Conflict of interest The authors declare that they have no conflict of tive predictive value; 10 out of 13 mutations that developed interest. HCM did not have pathological Q waves at baseline. Our study did not demonstrate a prognostic value of septal e′, Ethical approval All procedures performed in studies involving human in contrast to Ho et al. . The age difference between the participants were in accordance with the ethical standards of the insti- tutional and/or national research committee and with the 1964 Helsinki studies (16 vs 41 years) and differences in genetic mutations declaration and its later amendments or comparable ethical standards. might explain this discrepancy. However, we did observe a predictive value of E/e′ ratio, which supports the suggestion Informed consent Informed consent was obtained from all individual that diastolic dysfunction is a primary phenotypic feature participants included in the study. of HCM [28, 30]. Open Access This article is distributed under the terms of the Crea- tive Commons Attribution 4.0 International License (http://creat iveco Technical challenges associated with AMVL mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- measurement by echocardiography tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Previous studies most commonly used magnetic resonance Creative Commons license, and indicate if changes were made. imaging to measure AMVL length [6–8, 10]. Since transtho- racic echocardiography is the advised imaging modality in HCM clinical screening strategies and has a higher spatial References and temporal resolution than cardiac magnetic resonance 1. Semsarian C, Ingles J, Maron MS, Maron BJ (2015) New perspec- imaging [31, 32], we used echocardiography to determine tives on the prevalence of hypertrophic cardiomyopathy. J Am AMVL length. 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Ho CY, Cirino AL, Lakdawala NK, Groarke J, Valente AM, Sem- 33(11):1665–1675 sarian C, Colan SD, Orav EJ (2016) Evolution of hypertrophic 15. Nagueh SF, Bierig SM, Budoff MJ, Desai M, Dilsizian V, Eidem cardiomyopathy in sarcomere mutation carriers. Heart. https :// doi.org/10.1136/heart jnl-2016-31001 5 B, Goldstein SA, Hung J, Maron MS, Ommen SR, Woo A (2011) American society of echocardiography clinical recommendations 1 3 224 Journal of Ultrasound (2018) 21:217–224 29. Lakdawala NK, Thune JJ, Maron BJ, Cirino AL, Havndrup O, gene carriers: a study using speckle tracking echocardiography. Bundgaard H, Christiansen M, Carlsen CM, Dorval JF, Kwong Echocardiography 30(5):558–563 RY, Colan SD, Kober LV, Ho CY (2011) Electrocardiographic 31. Lin E, Alessio A (2009) What are the basic concepts of temporal, features of sarcomere mutation carriers with and without contrast, and spatial resolution in cardiac CT? J Cardiovasc Com- clinically overt hypertrophic cardiomyopathy. Am J Cardiol put Tomogr 3(6):403–408 108(11):1606–1613 32. To AC, Flamm SD, Marwick TH, Klein AL (2011) Clinical utility 30. Kauer F, van Dalen BM, Michels M, Soliman OI, Vletter WB, of multimodality LA imaging: assessment of size, function, and van Slegtenhorst M, ten Cate FJ, Geleijnse ML (2013) Diastolic structure. JACC Cardiovasc Imaging 4(7):788–798 abnormalities in normal phenotype hypertrophic cardiomyopathy Affiliations 1 1 1 1 Hannah G. van Velzen · Arend F. L. Schinkel · Myrthe E. Menting · Annemien E. van den Bosch · Michelle Michels * Hannah G. van Velzen Department of Cardiology, Thorax-center, Erasmus firstname.lastname@example.org Medical Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands 1 3
Journal of Ultrasound – Springer Journals
Published: Jun 6, 2018
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