Abnormal septal convexity into the left ventricle occurs in subclinical hypertrophic cardiomyopathy

A collaborative group at the Heart Hospital (University College London, United Kingdom) have previously created and published a case–control cohort [7] composed of G + LVH- HCM participants matched to healthy volunteers on the basis of age (±8 years), sex, body surface area (BSA ±10 %), and ethnicity. Inclusion criteria for the G + LVH− group included: (1) maximal LV wall thickness <13 mm by CMR and mass within the normal range relative to BSA, age, and sex; (2) sinus rhythm, no LVH, and no pathological Q waves/T-wave inversion on 12-lead electrocardiography; and (3) no causes of secondary LVH (valve disease, hypertension). Healthy volunteers had no history of cardiovascular disease or hypertension, a normal physical examination, no family history of inheritable cardiomyopathy or sudden cardiac death, and no personal history of cardiac symptoms or cardiovascular disease (including hypertension) and with a normal physical examination and ECG. Exclusion criteria for all participants were the presence of conventional contraindications for CMR, claustrophobia, and arrhythmias (e.g., atrial fibrillation, frequent atrial or ventricular ectopics). An ethics committee of the UK National Research Ethics Service approved the generic analysis of anonymized clinical scans. The genotyping project was approved by the UCL/UCLH Joint Research Ethics Committee. All participants gave written informed consent conforming to the Declaration of Helsinki (fifth revision, 2000). Study data were collected and managed using REDCap electronic data capture tool (Research Electronic Data Capture, REDCap Software - Version 5.9.6, http://​www.​project-redcap.​org/​).

Standard 12-lead electrocardiography was performed in the supine position during quiet respiration. LVH was evaluated with the Romhilt-Estes [21] and electrocardiographic European criteria [22, 23]. Electrocardiographic images were analyzed by an experienced observer blinded to clinical and CMR data.

Genomic analysis of this cohort has been previously described in detail [7, 24, 25]. G+ individuals were defined as the ones carrying a known disease causing mutation in one of the following sarcomere genes: myosin-binding protein C (MYBPC3), β-myosin heavy chain (MYH7), troponin T (TNNT2), troponin I (TNNI3), myosin regulatory light chain (MYL2), myosin essential light chain (MYL3), tropomyosin (TPM1), and cardiac α-actin (ACTC1).

Standard clinical scans (localizers, 3 long-axis views, black and white blood images, full LV short-axis stack) were performed using a 1.5-T magnet (Avanto, Siemens Medical Solutions®, Erlangen, Germany). CMR short-axis volumetric studies [26] were acquired from retrospectively gated, breath-held, balanced, steady-state free-precession cines (slice thickness, 7 mm; interslice gap, 3 mm; flip angle, 60°–80°; repetition time, 3.0 ms; echo time, 1.33 ms; field of view read typically, 380 mm; phase resolution, 75 %; typical acquired voxel size, 1.5 × 1.7 mm; 12 lines per segment). Late gadolinium enhancement images acquired through an inversion recovery turbo fast low-angle shot sequence were obtained 7 to 15 min after injection of 0.1 mmol/kg gadolinium-diethylenetriamine penta-acetic acid.

The morphology, systolic function and the structure of the LV were evaluated by cardiologists experienced in CMR (PR, MM). All CMR measurements were blinded to gene status. The presence of fibrosis and the structure of the LV were evaluated by other cardiologists experienced in CMR (JCM, GC, DMS).

LV volumes, LV ejection fraction (EF), LV outflow tract diameter, and LV mass were determined according to standardized CMR methods [27] (papillary muscles were included in the LV mass). LV wall thickness was measured at the septum and posterior wall on end-diastolic short-axis cine frames. The ratio of maximal septal diastolic wall thickness to posterior wall thickness was calculated, as well as relative wall thickness according to echocardiographic guidelines [11].

The convexity of the interventricular septum into the LV was measured from the apical 4-chamber view as the maximal distance between LV septal endocardial border at mid LV level and a line connecting mid-wall points at the level of tricuspid valve insertion and at the level of apical right ventricular (RV) insertion on the LV (Fig. 1). Septal convexity (SCx) was expressed positively. In case of concavity (corresponding to convexity into the RV – the normal arrangement), the measure was expressed negatively. In addition, on the 3 consecutive short axis views at papillary muscle level, an evaluation of the septal convexity was performed measuring the maximal distance between LV endocardial border and a reference line joining the epicardium of the LV-RV insertion points (B to A) (Fig. 2).

LV mitral angle, mitral papillary muscles angle, and LV-aortic root angle were analyzed on the open source software OsiriX® (http://​www.​osirix-viewer.​com) as previously described [20]. The angle between LV outflow tract and basal septum was also analyzed. Left ventricular end-diastolic sphericity index was measured (as previously described), as the ratio of LV end-diastolic diameter measured in short axis view at papillary muscle level (septal to lateral wall distance) divided by the LV end-diastolic long axis diameter measured in the apical 4 chamber view [12]. LV end-diastolic and end-systolic eccentricity indexes were calculated in the short-axis at the level of papillary muscles as the ratio of septal to lateral wall distance divided by inferior to anterior wall distance [11].

LV end-systolic left atrial areas were measured by planimetry on 4-chamber view. Anterior mitral valve leaflet (AMVL) length was measured using the method previously described by Maron et al. [2] Additionally, the mitral valve annulus was measured in mid diastole in the apical 3 chamber view. The 3 long-axis views and a modified 2-chamber view (transecting RV insertion points) were evaluated for the presence of myocardial crypts defined as focal myocardial defects with a depth of ≥50 % of the adjacent myocardium [5].

Descriptive data were analyzed for normality using the Shapiro-Wilks test and were expressed as mean ± standard deviation except where otherwise stated. Categorical variables were compared using χ² tests. Non-categorical data were directly compared using paired t test. An optimal threshold value for SCx within this case–control population was calculated as the Youden Index derived from the area under the receiver operating characteristics curve. Mean variability within and between readers was evaluated using the mean of differences between two measurements. Paired measurements for repeatability of SCx were evaluated using the Bland–Altman method [28]. A 2-sided p value <0.05 was considered significant. Statistical analysis was performed using SPSS for Windows version 20.0 (Chicago, IL).