Background
Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy, fiber disarray, and fibrosis interfering with myocardial force generation and relaxation. Because conventional Doppler echocardiographic methods inadequately assess diastolic function in HCM, the aim of this study was to determine local and global left ventricular (LV) relaxation mechanics in patients with HCM.
Methods
Seventy-two patients with HCM and 32 normal controls were studied. Using Velocity Vector Imaging, longitudinal and circumferential strain, strain rate, and rotation at the base, middle, and apex of the septal and lateral LV walls were measured. Differences between patients’ functional class subgroups were assessed using analysis of variance, and Tukey’s post hoc analysis was used to compare patients in HCM clinical subgroups with normal controls.
Results
Longitudinal strain and systolic and early diastolic strain rates were lower than normal in patients with HCM, whereas their circumferential values were higher. This suggests that shortening and relaxation orientation in HCM was more circumferential. The ratio of peak early diastolic to peak systolic strain rate decreased longitudinally and circumferentially in moderately to severely symptomatic (New York Heart Association class III or IV) patients (0.95 ± 0.35 vs 0.89 ± 0.35, P < .001). LV untwist was similarly prolonged in all HCM subgroups. LV relaxation assessed using the early apical reverse rotation fraction was significantly lower in patients with worse functional status (34 ± 14% vs 18 ± 4% in class I or II vs class III or IV). Left atrial volume increased, paralleling the severity of symptoms and the degree of diastolic dysfunction.
Conclusions
The evaluation of biplane myocardial mechanics offers new insights into the evaluation of diastolic function and its relationship to clinical status.
Hypertrophic cardiomyopathy (HCM) is a primary autosomal dominant disorder of the myocardium. It is related to >400 disease-causing mutations in 13 genes encoding cardiac contractile proteins. HCM is associated with myocardial hypertrophy, disarray, increased loose connective tissue, and fibrosis that may interfere with myocardial force generation as well as its relaxation. A large fraction of patients with HCM experience heart failure symptoms despite normal-appearing systolic function and without obstruction to left ventricular (LV) outflow. This emphasizes the importance of myocardial relaxation and LV filling in symptom generation in this disorder. The origin of diastolic dysfunction in HCM is multifactorial, with changes at the molecular (mutations, calcium economy and sensitivity), myocardial tissue (hypertrophy, fibrosis, and disarray), and global (geometry, ischemia) LV levels. Left atrial (LA) volumes in patients with HCM have been previously shown to relate to LV filling pressures. However, the precise quantitation of LV filling pressures by Doppler echocardiographic methods has major limitations due to the overwhelming effects of abnormal relaxation.
Two-dimensional (2D) deformation analysis is a tool to quantify regional and global ventricular mechanics. Myocardial displacement and velocity (longitudinal, circumferential, and rotation), strain, and strain rate are readily measured using 2D tissue tracking. This study was focused on diastolic mechanics and is a counterpart to our previous study on systolic mechanics in HCM. We used 2D strain imaging to analyze myocardial tissue displacement in the long and short axes to evaluate myocardial mechanics and to define local and global diastolic LV mechanics in patients with HCM. We also sought to determine the relationship between myocardial mechanics, the presence of LV outflow tract (LVOT) obstruction, and clinical status.
Methods
Study Population
We retrospectively studied 94 adult patients (aged >16 years) with HCM who had clinical and echocardiographic evaluations between January 2002 and December 2005 at the Toronto General Hospital. HCM was diagnosed by the echocardiographic finding of asymmetric septal hypertrophy (maximal septal thickness > 13 mm and a ratio of septal to posterior wall thickness ≥ 1.3), in the absence of another cardiac or systemic disease causing LV hypertrophy. This study was confined to patients with normal LV systolic function on echocardiography (ejection fraction ≥ 60%). Technically, included patients had to have stored Digital Imaging and Communications in Medicine echocardiographic studies, with a minimum 2D frame rate of 40 frames/s and good demarcation of the LV endocardial border. Patients with systemic hypertension, epicardial coronary artery disease, bundle branch blocks, right ventricular pacing, or previous invasive interventions were excluded, leaving 72 patients for analysis. The control group consisted of 32 healthy subjects without family histories of HCM, with normal clinical and echocardiographic findings. The study was approved by the Research Ethics Board of the Toronto General Hospital.
Clinical Data
Data were obtained from patients’ hospital records, including demographic data, symptoms, New York Heart Association (NYHA) functional class, family history, and medications at the time of index echocardiography. Follow-up invasive interventions to alleviate LVOT obstruction were recorded.
Doppler Echocardiographic Studies
Echocardiographic studies were interpreted by a cardiologist blinded to patients’ clinical findings. Two-dimensional, Doppler, and Doppler tissue imaging parameters were measured according to the guidelines of the American Society of Echocardiography. Patients with HCM were subclassified on the basis of their hemodynamic status as obstructive (resting or provocable LVOT gradient ≥ 30 mm Hg) or nonobstructive (resting and provocable LVOT gradient < 30 mm Hg).
Strain, Strain Rate, and Rotation Evaluation
Measurements were performed using Velocity Vector Imaging (VVI) software version 1.0 (Siemens Medical Systems, Mountain View, CA) from archived studies. Circumferential strain, strain rate, and radial and rotation velocities and angles were measured in 3 parasternal short axis planes (basal, mid, and apical) in the septal and lateral walls. Longitudinal septal and lateral wall strain and strain rates were measured from the apical 4-chamber view, at the base, middle, and apex. Positive radial strain (thickening) calculations were not available in this version of the VVI software.
Ventricular Twist
Averaged myocardial rotation angles were used to calculate LV twist, defined as the maximal instantaneous basal-to-apical angle difference. Rotation and twist timing was standardized to cycle length.
Diastolic Mechanics
Systolic and early diastolic peak strain rates were measured in the longitudinal and circumferential axes. We showed in our previous report that peak systolic and early diastolic strain rates were both lower longitudinally and higher circumferentially. Assuming that systolic and diastolic functions thus interrelate, we needed a new parameter to identify systolic-independent diastolic abnormalities. The ratio of peak early diastolic to peak systolic strain rate ratio (SR E/S ratio) was calculated ( Figure 1 A) to assess whether diastolic and systolic extent of changes were disproportionate.
We used early apical reverse rotation to assess early LV relaxation. We measured the fractional decrease in rotation angle from its peak value to its value at 10% of the cycle length later, using the following equation ( Figure 1 B):
EARRF = peak − t ( peak ) + 10 % CL peak ,
To assess overall early and late diastole, we measured untwist time, which was defined as the time difference (percentage cycle length) between peak twist to the time of its diastolic trough ( Figure 1 C).
Interobserver and Intraobserver Variability
Offline 2D strain evaluations were done by a single observer (S.C.). Twenty studies were reanalyzed by the same observer and another observer (H.Y.) for the assessment of intraobserver and interobserver variability.
Statistical Analysis
Continuous data are reported as mean ± SD. Patients and controls were compared using unpaired t tests. Comparisons among the HCM subgroups (ie, NYHA class I or II vs class III or IV, obstructive vs nonobstructive) were done using Wilcoxon’s rank-sum test. Differences between controls and patient subgroups were assessed using analysis of variance with Tukey’s post hoc analysis.
All statistical analyses were performed using SPSS version 12.0 (SPSS, Inc, Chicago, IL). Statistical significance was defined as a P value < .05. Correlation coefficients of observations and the 2 standard deviations of their mean percentage difference were used for interobserver and intraobserver variability assessment.
Results
Clinical and Echocardiographic Features
The HCM and control groups were similar in terms of age, gender, and body surface area. Although most of the patients with HCM were on β-blocker therapy, heart rates at the time of echocardiography were similar in patients not on therapy and controls. Forty-six patients (64%) had LVOT obstructions. Compared with controls, patients with HCM had increased septal thickness and LV mass, smaller LV end-systolic volumes, and greater indexed LA volumes ( Table 1 ). Traditional Doppler methods of assessing diastolic function ( Table 2 ) showed no differences in mitral early and atrial filling velocities, with slightly longer deceleration and isovolumic relaxation times in patients with HCM compared with controls. However, patients with obstructive HCM had higher mitral E-wave and A-wave velocities as well as longer deceleration times compared with those with nonobstructive HCM. In addition, compared with controls, patients with HCM had decreased Doppler tissue imaging early diastolic velocities and higher E/E′ ratios.
| Normal controls | Patients with HCM | ||
|---|---|---|---|
| Variable | (n = 32) | (n = 72) | P |
| Clinical | |||
| Age (y) | 49 ± 18 | 43 ± 14 | NS |
| Men | 16 (50%) | 50 (69%) | NS |
| Body surface area (m 2 ) | 1.9 ± 0.2 | 1.9 ± 0.2 | NS |
| β-blocker therapy | 0 (0%) | 62 (86%) | |
| Heart rate (beats/min) | 71 ± 12 | 66 ± 14 | NS |
| 2D echocardiography | |||
| LV diastolic volume (cm 3 ) | 96 ± 22 | 87 ± 24 | <.05 |
| LV systolic volume (cm 3 ) | 31 ± 11 | 22 ± 14 | <.005 |
| LV mass (g) | 185 ± 52 | 339 ± 136 | <.0005 |
| IVS thickness (cm) | 1.0 ± 0.2 | 2.0 ± 0.6 | <.0005 |
| PW thickness (cm) | 0.9 ± 0.1 | 1.0 ± 0.2 | <.005 |
| Ejection fraction (%) | 67 ± 8 | 75 ± 11 | <.005 |
| LA systolic diameter (cm) | 3.6 ± 0.6 | 4.2 ± 0.6 | <.0005 |
| LAVi (cm 3 /m 2 ) | 23 ± 5 | 37 ± 13 | <.0005 |
| Gradient | |||
| LVOT gradient at rest (mm Hg) | 6 ± 2 | 34 ± 33 | <.0005 |
| LVOT gradient after amyl nitrite | Not done | 59 ± 41 |
| Patients with HCM | ||||
|---|---|---|---|---|
| Normal controls | All | Nonobstructive | Obstructive | |
| Variable | (n = 32) | (n = 72) | (n = 26) | (n = 46) |
| NYHA functional class | 1 ± 0 | 1.8 ± 0.8 | 1.4 ± 0.6 | 2.0 ± 0.9 † |
| Diastology | ||||
| Mitral E-wave velocity (cm/s) | 0.74 ± 0.14 | 0.79 ± 0.25 | 0.73 ± 0.19 | 0.82 ± 0.27 † |
| Mitral A-wave velocity (cm/s) | 0.64 ± 0.17 | 0.61 ± 0.22 | 0.53 ± 0.13 | 0.66 ± 0.25 † |
| Mitral E deceleration time (ms) | 200 ± 34 | 226 ± 56 ∗ | 194 ± 39 | 243 ± 57 † |
| IVRT (ms) | 74 ± 13 | 89 ± 20 ∗ | 86 ± 14 ‡ | 91 ± 22 |
| Pulmonary vein S/D ratio | 1.3 ± 0.5 | 1.3 ± 0.5 | 1.2 ± 0.3 | 1.4 ± 0.5 † |
| LAVi (cm 3 /m 2 ) | 23 ± 5 | 37 ± 13 ∗ | 32 ± 10 ‡ | 41 ± 13 † |
| E/E′ ratio | 6 ± 2 | 10 ± 6 ∗ | 7 ± 3 | 12 ± 6 † |
| Longitudinal | ||||
| Strain (%) | −21 ± 4 | −16 ± 4 ∗ | −17 ± 5 ‡ | −15 ± 5 † |
| Systolic strain rate (%/s) | −1.1 ± 0.3 | −0.8 ± 0.2 ∗ | −0.9 ± 0.2 ‡ | −0.8 ± 0.2 † |
| Early diastolic strain rate (%/s) | 1.1 ± 0.5 | 0.8 ± 0.3 ∗ | 0.9 ± 0.4 ‡ | 0.7 ± 0.3 † |
| Circumferential | ||||
| Strain (%) | −29 ± 8 | −34 ± 9 ∗ | −32 ± 9 ‡ | −33 ± 9 |
| Systolic strain rate (%/s) | −1.5 ± 0.6 | −2.0 ± 0.8 ∗ | −1.9 ± 0.7 ‡ | −2.0 ± 0.8 |
| Early diastolic strain rate (%/s) | 1.4 ± 0.6 | 1.9 ± 0.9 ∗ | 1.8 ± 1.0 ‡ | 1.9 ± 0.8 |
| Diastolic-to-systolic SR ratio (%) | ||||
| Longitudinal E/S | 1.01 ± 0.32 | 0.93 ± 0.35 ∗ | 1.00 ± 0.37 | 0.88 ± 0.31 † |
| Circumferential E/S | 0.99 ± 0.31 | 0.95 ± 0.34 ∗ | 0.97 ± 0.39 | 0.93 ± 0.33 |
| Combined E/S | 1.02 ± 0.32 | 0.94 ± 0.35 ∗ | 0.99 ± 0.38 | 0.90 ± 0.32 † |
| Twist (base-apex) (°) | 6.6 ± 3.2 | 7.0 ± 2.8 | 6.9 ± 2.6 | 7.0 ± 3.0 |
| Twist time (percentage cycle length) | 41 ± 8 | 37 ± 9 ∗ | 36 ± 10 ‡ | 37 ± 8 |
| Untwist time (percentage cycle length) | 36 ± 8 | 46 ± 9 ∗ | 45 ± 9 ‡ | 48 ± 9 † |
| EARRF (%) | 37 ± 10 | 34 ± 14 | 36 ± 15 | 33 ± 13 |
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