Summary
Background
Hypertrophic cardiomyopathy (HCM) causes various degrees of fibrosis resulting in left ventricular function impairment, which can be measured using mitral annular plane systolic excursion (MAPSE).
Aims
To determine the values for septal, lateral and average MAPSE using cardiovascular magnetic resonance (CMR) in healthy controls and patients with HCM; and to investigate whether MAPSE correlated with the extent of fibrosis.
Methods
Patients with HCM and healthy controls underwent CMR.
Results
In 50 healthy controls, septal and lateral MAPSE were comparable and showed excellent intra- and inter-observer reliability. Patients with HCM had significantly reduced septal, lateral and average MAPSE compared to healthy controls. Furthermore, in patients with HCM, septal MAPSE measurements were significantly reduced compared to lateral ones. Correspondingly, the septal myocardial segments showed significantly more late gadolinium enhancement (LGE) than lateral ones. No significant differences were found between echocardiographic and CMR MAPSE measurements in healthy controls and patients with HCM. Patients who suffered a major adverse cardiac event or stroke revealed a significantly reduced MAPSE and a significantly greater LGE extent compared to event-free patients with HCM.
Conclusions
MAPSE measurement using CMR is feasible, reproducible and comparable to echocardiography in healthy controls and patients with HCM. The asymmetric and mainly septal distribution of myocardial hypertrophy and fibrosis detected by LGE in patients with HCM was reflected by significantly reduced septal versus lateral MAPSE. Therefore, reduced MAPSE seems to be an easily determinable marker of fibrosis accumulation leading to left ventricular mechanical dysfunction and also seems to have a prognostic implication.
Résumé
Contexte
La cardiomyopathie hypertrophique (CMH) est une maladie d’origine génétique. L’ampleur des cicatrices myocardiques est variable et affecte la fonction systolique et diastolique du ventricule gauche de ces patients. L’excursion systolique dans le plan de l’anneau mitral (MAPSE) représente une mesure rapide et simple qui traduit le raccourcissement longitudinal du ventricule gauche et donne également des informations sur la fonction diastolique.
Objectif
Le but de cette étude était d’établir des valeurs de références pour la mesure du MAPSE à l’anneau mitral septal (MAPSE septal) et à l’anneau mitral latéral (MAPSE latéral) ainsi que la moyenne des deux mesures (MAPSE moyen) en utilisant l’imagerie par résonance magnétique (IRM) sur des sujets contrôle sains. Nous avons comparés les mesures de MAPSE des sujets contrôle avec ceux de patients porteurs d’une CMH. De plus, nous avons corrélé le MAPSE avec l’ampleur des cicatrices myocardiques.
Méthodes
Exploration par IRM sur 88 patients porteurs d’une CMH et 50 sujets contrôle sains.
Résultats
Les MAPSE septal et latéral ont été comparables et présentaient une excellente fiabilité intra- et interobservateur dans le groupe contrôle sain. De plus, les mesures de MAPSE ne montraient pas de différence significative entre échocardiographie et IRM chez les porteurs d’une CMH et les sujets contrôle sains. Les patients porteurs d’une CMH montraient une considérable réduction des mesures de MAPSE septal, latéral et moyen comparés aux sujets sains. De plus, la mesure du MAPSE septal était considérablement diminuée en comparaison de celle du MAPSE latéral chez les patients porteurs d’une CMH. De plus, les segments myocardiques septaux montraient plus de cicatrices myocardiques comparés aux segments myocardiques latéraux. Les porteurs d’une CMH souffrant d’un événement adverse majeur (mort ou greffe cardiaque, tachycardie ventriculaire) ou d’une attaque apoplexie montraient des mesures de MAPSE considérablement diminuées ainsi qu’un rehaussement tardive plus étendu comparé aux porteurs d’une CMH sans événements.
Conclusions
La mesure du MAPSE par l’utilisation de l’IRM est faisable, fiable et comparable à celle de l’échocardiographie sur des sujets sains ainsi que sur les porteurs d’une CMH. La distribution septale de l’hypertrophie et des plages de rehaussement tardif a été identifiée par une considérable diminution des mesures du MAPSE septal par rapport au MAPSE latéral. Une diminution du MAPSE pourrait donc représenter une mesure simple pour identifier les cicatrices myocardiques dans la CMH et semble avoir un rôle pronostique défavorable.
Background
Hypertrophic cardiomyopathy (HCM) is a complex form of genetic heart disease. Macroscopically, HCM is characterized by marked, frequently asymmetrical left ventricular hypertrophy in the absence of other causes, such as hypertension or valve disease. Histopathologically, it is associated with cardiomyocyte and cardiac hypertrophy, myocyte disarray, interstitial and replacement fibrosis, and dysplastic intramyocardial arterioles, which are all thought to interfere with myocardial force generation and relaxation . Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is able to visualize myocardial fibrosis associated with left ventricular systolic and diastolic dysfunction.
Mitral annular plane systolic excursion (MAPSE) can easily be assessed echocardiographically and correlates with systolic longitudinal ventricular systolic function, parameters of diastolic function (such as early diastolic filling/early diastolic mitral annular velocity [E/E′] and mitral flow propagation velocity) as well as left ventricular twist and torsion . MAPSE can be determined either on the lateral or septal annular site or is given as the average between the measurements at the septal and lateral annular site .
In HCM, regions most affected by the hypertrophic process are the septum and the base . Furthermore, myocardial fibrosis is known to be most pronounced at the junction of the septum and the left ventricular and right ventricular free wall where myofibrillar disarray is maximal . Therefore, we assumed that the septal MAPSE would be most affected.
To date, there are no data available on MAPSE measurements using state of the art CMR, and cut-off values are derived from echocardiography. Thus, the primary aim of our study was to determine the values for septal, lateral and average MAPSE in healthy controls using CMR. Secondly, we determined these values in patients with HCM and compared them among patient subgroups and to healthy controls. Thirdly, we investigated whether MAPSE correlated with the extent of fibrosis.
Methods
Study population
Consecutive patients with HCM referred for CMR were enrolled between January 2004 and December 2012 at our hospital. The population included 45 patients as reported earlier . All patients with HCM were diagnosed based on conventional criteria: left ventricular hypertrophy ≥ 15 mm on two-dimensional echocardiography in the absence of another disease that could account for the hypertrophy . Hypertrophic non-obstructive cardiomyopathy (HNCM) was defined as a pressure gradient ≤ 30 mmHg at rest and after provocation. Patients with a pressure gradient > 30 mmHg at rest or after provocation were classified as having hypertrophic obstructive cardiomyopathy (HOCM).
Age- and sex-matched healthy subjects served as controls and satisfied the following criteria: normal physical examination, normal blood pressure (< 130/85 mmHg), normal electrocardiographic findings, no history of chest pain or dyspnoea, no diabetes, no hyperlipidaemia and normal two-dimensional echocardiography and Doppler examination. None of the control subjects was on medication. Exclusion criteria for healthy controls were: the presence of signs or symptoms of cardiac diseases, hypertension or diabetes; smoking; or participation in competitive sports.
The study design complied with the declaration of Helsinki and was approved by local ethical committee, Medical Ethic Commission II, Faculty of Medicine Mannheim, University of Heidelberg, Germany. Written informed consent was obtained from all participants and data were analysed anonymously.
CMR image acquisition
All studies were performed using a 1.5-Tesla whole body imaging system (Magnetom Avanto and Sonata, Siemens Medical Systems, Healthcare Sector, Erlangen, Germany) using a four-element (Sonata) or six-element (Avanto) phased-array body coil.
Cine images were acquired using a retrospective electrocardiographic-gated, balanced segmented steady state free precession (trueFISP) sequence in three long-axis views (2-, 3-, and 4-chamber views) and in multiple short-axis views, covering the entire left ventricle from base to apex. LGE images were obtained 10–15 minutes after intravenous administration of 0.2 mmol/kg gadoteric acid (Dotarem, Guerbet, Roissy CdG Cedex, France), using an inversion recovery turbo Fast Low Angle Shot sequence at the same position as the long- and short-axis cine acquisitions in end-diastole . The inversion time was adjusted by patient to optimally null the signal from normal myocardium, typically 250–300 ms.
CMR image analysis
Left ventricular mass and volumes as well as right ventricular and left atrial volumes were determined using CMR as previously described. The left ventricular remodelling index (LVRI) was determined as the ratio of left ventricular end-diastolic mass (LV-EDM) to left ventricular end-diastolic volume (LV-EDV) . MAPSE measurements were assessed on four-chamber view cine images. The distance between the basal septal mitral annulus (septal MAPSE), the basal lateral mitral annulus (lateral MAPSE) and a reference point outside the left ventricular apex was measured in end-diastole and end-systole. The distance travelled by the septal and lateral annulus from end-diastole to end-systole was calculated as septal and lateral MAPSE by subtracting the left ventricular end-systolic length (LVESL) from the left ventricular end-diastolic length (LVEDL) as shown on Fig. 1 . Average MAPSE was calculated as the average of septal and lateral MAPSEs.
LGE quantification
The extent of LGE was quantified visually using the standard left ventricular 17-segment model . Each segment was visually scored for the total extent of LGE as previously described . The 17 segments were grouped into four cardiac regions:
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anterior region, including segments 1, 7, 13 and 17;
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septal region, including segments 2, 3, 8, 9, 14 and 17;
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posterior region, including segments 4, 10, 15 and 17;
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lateral region, including segments 5, 6, 11, 12, 16 and 17.
To determine the LGE extent in the septal and lateral regions, the scores of these segments were summed. The resulting septal and lateral LGE extents were then expressed as a percentage of the maximum possible score of 24.
Echocardiography
In 20 randomly selected HCM patients, a retrospective analysis of the transthoracic echocardiograms (TTEs) obtained for clinical indications at the time of CMR examination using a commercially available ultrasound system (Vivid 7 or Vivid i, GE Ultrasound, Horten, Norway with a 2.5 MHz phased-array transducer) was performed. Additionally, a TTE analysis was performed in the first 20 healthy controls using the same ultrasound system. Standard echocardiographic images were obtained at end-expiratory apnoea. M-mode echocardiography through the mitral valve annulus, from the apical four-chamber view at both the septal and lateral annuli, was performed. The images were optimized for routine four-chamber view evaluation. The M-line was positioned through the medial and lateral annulus and included the tissue-blood border for easy identification of the motion of the annulus. The trough of the motion was defined as the end-diastolic position of the annulus, measured at the tip of the QRS complex. The peak was defined as the maximal systolic excursion point. All images were stored digitally and analysed offline by a single investigator blinded to CMR data using EchoPAC, GE Ultrasound.
Follow-up data and definition of study endpoints
Long-term follow-up was performed retrospectively by telephone contact. Reported clinical events were confirmed by review of the corresponding medical records in our electronic Hospital Information System or contact with the general practitioner, referring cardiologist or the treating hospital. The observer was unaware of the CMR results and collected data with a standardized questionnaire. The definition of major adverse cardiac event (MACE) required the documentation of cardiac death, heart transplantation or significant ventricular arrhythmia. In case of out-of-hospital death not followed by autopsy, sudden unexpected death was classified as cardiac death. Stroke was defined as neurological impairment and disability due to vascular causes lasting longer than 24 hours. Patients who had a stroke and suffered from a MACE over the course of follow-up were only counted regarding MACE.
Statistical analysis
Data are presented as mean ± standard deviation (with or without ranges) or counts and percentages. Continuous parameters were compared using a two-tailed student’s t -test. Pearson’s correlation was used to correlate septal, lateral and average MAPSE to the extent of LGE and to correlate the extent of LGE in septal regions to septal MAPSE and the extent of LGE in lateral regions to lateral MAPSE.
The level of agreement among the MAPSE measurements using CMR in healthy controls was evaluated using Bland–Altman analysis . Intra- and inter-observer variabilities were assessed and expressed as mean difference between two measurements (d = bias), the standard deviation (SD) of the differences, the limits of agreement (d ± 1.96 × SD) and the coefficient of variation (CV = 2 × SD) .
For septal, lateral and average MAPSE measurements, using either echocardiography or CMR, the interstudy reliability was assessed using Lin’s concordance correlation coefficient (CCC) in 20 randomly selected healthy controls as well as 20 randomly selected patients with HCM . A CCC value of 1 indicates perfect agreement; values < 0.5 were considered to be poor agreement; values between 0.5 and 0.7 to be moderate agreement; and values > 0.7 to be good to excellent agreement.
All results were considered statistically significant when P < 0.05. Analyses were performed with Statistical 1 Package for Social Sciences (SPSS for windows 14.0, Chicago, IL, USA).
Results
A total of 103 patients with HCM were enrolled during 2004–2012. Fifteen patients were excluded, due to incomplete clinical or CMR data ( n = 10) or insufficient CMR image quality ( n = 2 due to tachyarrhythmias, n = 3 due to difficulties in the angulation when planning the four-chamber view), yielding a total number of 88 patients finally included in this study. Baseline patient demographics and characteristics are presented in Table 1 . Fifty age- and sex-matched healthy subjects served as controls.
| All patients with HCM ( n = 88) | |
|---|---|
| Age (years) | 56 ± 13 |
| Men | 58 (65.9) |
| HCM | |
| HOCM | 37 (42.0) |
| HNCM | 51 (58.0) |
| Morphological features | |
| Asymmetrical septal hypertrophy | 76 (86.4) |
| Symmetrical hypertrophy | 8 (9.1) |
| Apical hypertrophy | 3 (3.4) |
| Midventricular hypertrophy | 1 (1.1) |
The CMR characteristics of patients with HCM and healthy controls are summarized in Table 2 . In healthy controls, septal and lateral MAPSE were comparable (1.28 ± 0.38 cm vs. 1.38 ± 0.40 cm; P = 0.3). Normal values for septal, lateral and average MAPSE were all approximately 0.9–2.5 cm ( Table 2 ). In 50 healthy controls, CMR-derived MAPSE measurements showed an excellent reproducibility. Intra- and inter-observer variability for all MAPSE measurements was low, as indicated by the small biases (d) and low CVs for each measurement ( Table 3 ).
| All patients with HCM ( n = 88) | Healthy controls ( n = 50) | P | |
|---|---|---|---|
| LVEF (%) | 61 ± 10 (29–85) | 60 ± 4 (55–67) | 0.86 |
| LV-EDVI (mL/m 2 ) a | 77 ± 21 (28–143) | 76 ± 12 (51–106) | 0.88 |
| LV-ESVI (mL/m 2 ) a | 32 ± 16 (10–96) | 31 ± 5 (21–38) | 0.83 |
| LV-SVI (mL/m 2 ) a | 45 ± 12 (14–88) | 45 ± 10 (29–70) | 0.97 |
| LV-EDMI (g/m 2 ) a | 98 ± 29 (51–182) | 60 ± 11 (41–75) | < 0.001 |
| LVRI (g/mL) | 1.34 ± 0.48 (0.73–3.84) | 0.88 ± 0.27 (0.44–1.7) | < 0.001 |
| LV EDD (mm) | 52 ± 7 (36–68) | 51 ± 5 (43–55) | 0.61 |
| SWT (mm) | 20 ± 5 (12–39) | 9 ± 2 (5–11) | < 0.001 |
| PWT (mm) | 10 ± 3 (5–22) | 9 ± 2 (5–10) | < 0.001 |
| Indexed LA volume (mL/m 2 ) a | 48 ± 21 (16–129) | 23 ± 3 (20–29) | < 0.001 |
| Septal MAPSE (cm) | 0.93 ± 0.33 (0.15–1.82) | 1.28 ± 0.38 (0.90–2.50) | < 0.001 |
| Lateral MAPSE (cm) | 1.08 ± 0.37 (0.36–2.07) | 1.38 ± 0.40 (0.90–2.50) | 0.001 |
| Average MAPSE (cm) | 1.00 ± 0.32 (0.29–1.74) | 1.33 ± 0.38 (0.95–2.50) | < 0.001 |
| Presence of LGE | 57 (64.8) | – | – |
| Total LGE extent (%) | 13 ± 15 (0–63) | – | – |
| Septal LGE extent (%) | 15 ± 18 (0–71) | – | – |
| Lateral LGE extent (%) | 6 ± 10 (0–33) | – | – |
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