Abstract
This study aimed to characterize cardiovascular magnetic resonance (CMR) tissue biomarkers in individuals with apical HCM (ApHCM) and assess their association with clinical outcomes. Firstly, CMR imaging-derived tissue characterization parameters, including T1 and T2 relaxation times, Extracellular volume (ECV), and extent of late gadolinium enhancement (LGE), was compared between patients with ApHCM and control patients. Secondly, composite outcome defined as non-sustained ventricular tachycardia detected on holter monitoring, implantation of an implantable cardioverter defibrillator (ICD), or hospitalization for heart failure were assessed amongst those with ApHCM. The study included 91 participants: 76 with ApHCM and 15 matched controls. Compared with controls, patients with ApHCM had higher apical T1 values (1057.2 ± 33.73 vs 1005.53±25.5 msec; p < 0.001), T2 apical values (53.44 ± 2.97 msec vs 48.26 ± 2.99 msec, p < 0.001), and apical ECV fraction (31.96 ± 2.61% vs 26.47 ± 1.32%, p < 0.001). Among ApHCM patients without LGE ( n = 38), increased apical T1, T2, and ECV values were identified in 86.5%, 75.8%, and 91.4% of cases, respectively. T2 maximal value above the 50th percentile was significantly associated with the combined endpoint (AdjOR 3.75, 95% CI: 1.10–15.08, p = 0.043), as well as the presence of LGE (AdjOR 8.31, 95% CI: 2.04–56.38, p = 0.009). In conclusion, in ApHCM, T1, T2, and ECV values were increased in the apical segments, even in the absence of LGE. Increased T2 values and the presence of LGE were significantly associated with clinical outcomes, suggesting that these imaging markers may contribute to risk stratification these patients.
Graphical Abstract
Apical hypertrophic cardiomyopathy (ApHCM) is a morphological subtype of HCM, characterized by unexplained left ventricular hypertrophy predominantly in the apex. The diagnosis is made when the left ventricular (LV) apex has an apical wall thickness of ≥15 mm, ≥13 mm in familial disease, a ratio of apical to basal LV wall thickness of ≥1.3 at end-diastole, or LV obliteration. Late consequences of ApHCM include apical aneurysms, heart failure, and ventricular arrhythmias. The advent of cardiac magnetic resonance (CMR) has enabled the reliable detection of tissue characteristics; however, there is sparse data on CMR tissue characterization parameters specific to ApHCM. CMR tissue characterization parameters, including T1 and T2 mapping, and extracellular volume (ECV), have been associated with poor clinical outcomes in HCM a but have not been explicitly investigated in patients with ApHCM. The aim of the present study was therefore to describe tissue mapping findings in ApHCM as compared to those in control subjects and to assess whether imaging biomarkers T1, T2 mapping, ECV, and LGE are associated with clinical outcomes in consecutive patients with ApHCM.
Methods
Study design and patient population
This retrospective cohort study included adult patients (aged >18 years) with ApHCM who underwent CMR between 2019 and 2022. Patients were identified from a dedicated HCM registry, and only those meeting the diagnostic criteria for ApHCM were included. Pure ApHCM was defined as maximum apical wall thickness ≥15 mm in end diastole, with apical wall thickness exceeding the basal. Relative ApHCM was defined as inappropriate apical hypertrophy compared to the expected apical wall thickness (loss of apical tapering, apical thickness > basal thickness) and <15 mm, alongside other characteristic features of the disease (distinctive ECG changes, apical cavity obliteration, or apical aneurysm). The control cohort were patients who underwent a CMR in the same time interval with normal findings and without evidence cardiovascular disease or ApHCM and matched for age and gender. Clinical and CMR imaging data were collected and analyzed retrospectively. Clinical variables, including demographics, comorbidities, and arrhythmic events, were extracted from the registry database.
CMR acquisition and data analysis
CMR measurements included LV dimensions, volumes, T1, T2, and ECV measurements. These measurements were compared with those of healthy control subjects. CMR imaging was performed using a 1.5T scanner (Ingenia; Philips Medical Systems), adhering to standardized imaging protocols. The CMR protocol included multiplanar cine imaging for assessing cardiac function, volumes, and mass, as well as LGE imaging for scar evaluation. Balanced steady-state free precession and single breath-hold modified inversion recovery Look-Locker (MOLLI) were employed for T1 mapping, while a navigator-gated black blood prepared gradient spin-echo sequence was utilized for T2 mapping. Native T1, T2 mapping, and postcontrast T1 mapping were acquired in three short-axis slices (apical, midventricular, and basal). ECV quantification was conducted from native T1 and postcontrast T1 mapping, with adjustments made for haematocrit value.
For data analysis, the complete dataset was transmitted to a dedicated CMR workstation (Philips Intellispace Portal, version 11.0). LV volumes, dimensions, and mass were measured using automated contour detection, with manual correction if necessary. Myocardial pre and postcontrast T1 and T2 relaxation times were measured at motion-corrected basal, mid, and apical slices by drawing a region of interest (ROI) that included all myocardial segments within the slice. Maximal and average values of T1, T2, and ECV were assessed in basal, mid, and apical slices ( Figure 1 ). Additionally, the ROI within the septal region of the midshort-axis slice was defined, as indicated by expert consensus documents. , For the assessment of T1, T2 relaxation times, and LGE, endo- and epicardial contours of the left ventricle were traced while excluding epicardial fat, pericardium, and blood from the analysis. Abnormal native T1 and T2 values were defined as greater than 1060 msec and greater than 57 msec, respectively. LGE was defined as an image intensity level ≥2 standard deviations above the mean of the remote myocardium. The amount of LGE was expressed as a percentage of LV myocardial mass, and the ECV was calculated based on pre and postcontrast T1 images.
Representative native T2 (upper row), T1 (middle row), and LGE (bottom row) in a patient with apical HCM. T2 and native T1 mapping indicated an increase in signal intensity from the base (panels A,D) to apical (panels C,F) slices. Negative LGE imaging was observed in all slices (G,H,I). Note the increase in apical T2 and T1 values, despite the absence of LGE.
Clinical outcomes
The clinical outcome was assessed amongst the cohort of patients with ApHCM. The combined clinical outcome was a composite of documented nonsustained ventricular arrhythmia on Holter monitoring or via an implantable loop recorder, the implantation of an implantable cardiac defibrillator, and/or hospitalization for heart failure during the study period. The abnormal CMR parameters were examined for their association with combined clinical outcomes during follow-up.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) if normally distributed, or median with interquartile range (IQR) if skewed. Categorical variables were presented as frequency (%). Continuous data were compared with the student’s t-test when normally distributed, and with a nonparametric Wilcoxon signed-rank test when normality was rejected by a QQ-plot. Categorical data were compared using chi-square or Fisher exact tests. Multivariable logistic regression models evaluated the association between myocardial tissue characterization parameters (T1, T2, and ECV) and the composite clinical outcome, with results presented as adjusted odds ratios (AdjOR) and 95% confidence intervals (CI). Receiver operating characteristic (ROC) curves were generated to assess the discriminative ability of continuous imaging variables, including T2 apical maximum values and LGE percentage, in predicting the composite outcome. The area under the curve (AUC) was calculated to determine the predictive performance of each parameter. All statistical analyses were performed using SPSS (Version 25) and R (Version 4.4.3).
Ethical approval was obtained for this study from the Rabin Medical Center Helsinki Committee.
Results
Clinical characteristics
Table 1 shows the baseline characteristics of 91 patients, including 76 patients with ApHCM and 15 controls. The controls were matched with no difference in age or gender, however, the ApHCM group had a significantly higher percentage of patients with hypertension.
Table 1
Baseline characteristics
| Variable | Apical HCM ( n = 76) | Controls ( n = 15) | p value |
|---|---|---|---|
| Male sex | 53 (69.7) | 11 (73.3) | 1.0 |
| Age, years | 59.4 (13.7) | 59.6 (7.6) | 0.956 |
| Body mass index kg/m 2 | 27.47 (4.81) | 26.35 (4.76) | 0.412 |
| Beta blocker | 25 (32.9) | 3 (20) | 0.311 |
| Calcium channel blocker | 21 (27.6) | 0 (0) | 0.027 |
| Family history of SCD | 18 (27.3) | 1 (6.7) | 0.173 |
| Hypertension | 36 (47.4) | 2 (13.3) | 0.009 |
| Diabetes mellitus | 10 (13.2) | 1 (6.7) | 0.668 |
| Coronary artery disease | 8 (10.5) | 0 (0) | 0.361 |
| Percutaneous coronary intervention | 3 (3.9) | 0 (0) | 1.000 |
| Coronary artery bypass surgery | 2 (2.6) | 0 (0) | 1.000 |
| Smoker | 16 (21.1) | 2 (13.3) | 0.638 |
| NYHA Class I | 34 (77.3) | 15 (100) | 0.128 |
| NYHA Class II | 9 (20.5) | 0 (0) | |
| NYHA Class III/IV | 0 (0) | 0 (0) | |
| Deep T-wave inversion on ECG | 65 (92.9) | 0 (0) | < 0.001 |
Values are mean ± Standard deviation or n (%).
HCM, hypertrophic cardiomyopathy; NYHA, New York Heart Association; SCD, sudden cardiac death.
Cardiac magnetic resonance- Ventricular volumes and tissue thickness
Compared with controls, patients with ApHCM had higher apical native T1 value (1057.2 ± 33.73 vs 1005.53±25.5 msec; p < 0.001), T2 apical values (53.44 ± 2.97 msec vs 48.26 ± 2.99 msec, p < 0.001), and apical ECV fraction (31.96 ± 2.61% vs 26.47 ± 1.32%, p < 0.001). In the ApHCM cohort, increased apical T1, T2, and ECV were observed in 89.3 %, 76.8%, and 93.1% of patients, respectively. Compared to controls, there was no significant difference in LVEDV index (65.36 ± 12.4 ml/m 2 vs 62.49 ± 11.2 mL/m 2, p = 0.407) but patients with ApHCM had markedly increased LV mass index (64.65 ± 21.83 vs 42.3 ± 9.49 g/m², p < 0.001). In apical HCM, 12 patients had an apical aneurysm; no patients had an apical thrombus ( Table 2 ).
Table 2
Cardiac magnetic resonance characteristics
| Variables | Apical HCM | Control | p value |
|---|---|---|---|
| n = 76 | n = 15 | ||
| Cardiac volumes and function | |||
| LVEDVI (mL/m 2) | 65.36 (12.4) | 62.49 (11.2) | 0.407 |
| LVESVI (mL/m 2) | 21.97 (8.19) | 21.97 (8.19) | 0.862 |
| LV mass Index (g/m 2) | 64.65 (21.83) | 42.3 (9.49) | < 0.001 |
| LVEF (%) | 67.11 (8.27) | 65.87 (5.4) | 0.58 |
| Left atrial area (cm 2) | 28.54 (4.65) | 24.84 (5.08) | 0.007 |
| Right atrial area (cm 2) | 24.72 (4.63) | 24.07 (4.08) | 0.611 |
| Apical aneurysm | 12 (15.8) | 0 (0) | 0.217 |
| Tissue mapping | |||
| Apical T1, average (msec) | 1057.2 (33.7) | 1005.53 (25.5) | 0.001 |
| Apical T1, maximum (msec) | 1090.9 (38.6) | 1044.2(83.89) | < 0.001 |
| Septal T1 (msec) | 1030.1 (41.1) | 1.018.5 (27.67) | 0.318 |
| Apical ECV, average (%) | 32.0 (2.6) | 26.47 (1.3) | < 0.001 |
| Apical ECV, maximum (%) | 34.6 (3.1) | 27.85 (1.26) | < 0.001 |
| Septal ECV (%) | 30.2 (3.5) | 27.09 (1.9) | 0.002 |
| Apical T2, average (msec) | 53.4 (3.0) | 48.26 (2.99) | < 0.001 |
| Apical T2, maximum (msec) | 57.1 (4.1) | 50.31 (2.21) | < 0.001 |
| Septal T2 (msec) | 51.6 (3.5) | 48.11 (3.37) | 0.001 |
| LGE ≥ 5 % | 10 (13.2) | 0 (0) | 0.043 |
| LGE, percentage of myocardium (%) | 38 (50) | 0 (0) | < 0.001 |
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