Background
The aim of this study was to evaluate whether maximal left atrial (LA) volume and phasic atrial function would be further altered in patients with hypertrophic cardiomyopathy (HCM) compared with patients with systemic hypertension (HT) with similar left ventricular (LV) mass. LA enlargement on echocardiography has been documented in HCM and moderate or severe HT, both conditions causing LV hypertrophy.
Methods
Thirty-five patients with HCM were compared with patients with HT matched for LV mass and normal controls matched for age and gender. Maximal, minimal, and pre-“p” LA biplane and real-time 3-dimensional volumes and LA phasic function were evaluated. Atrial function was estimated by LA ejection force, atrial fraction, and A′ velocity.
Results
Maximal, minimal, and pre-“p” LA volumes were significantly increased in the HCM group compared with the HT group and controls. Additionally, LA phasic volumes demonstrated that conduit volume and total, passive, and active emptying fractions were decreased in the HCM group. Despite similar LV mass, the HCM group had a higher incidence of abnormal diastolic filling (60% vs 34%, P = .001).
Conclusions
Patients with HCM appeared to have larger LA volumes, poorer LA function, and greater severity of diastolic dysfunction compared with those with HT having comparable LV mass. LA changes may be due to coexistent atrial myopathy associated with other pathophysiologic aspects of HCM, including outflow obstruction, mitral regurgitation, and myocardial fibrosis in HCM.
Hypertrophic cardiomyopathy (HCM) is an inherited disorder with complex pathophysiology including, left ventricular (LV) outflow tract (LVOT) obstruction, mitral regurgitation, and an increased incidence of arrhythmias. LV hypertrophy (LVH) and increased LV mass are the signature findings in HCM, with diastolic dysfunction more common than systolic dysfunction.
In normal populations, left atrial (LA) volume is a marker of diastolic dysfunction and its severity. LA enlargement consequent to LVH correlates with morbidity and mortality and predisposes to atrial arrhythmias in both hypertension (HT) and HCM.
The aim of this study was to evaluate LA volumes and phasic function in patients with HCM and HT with similar LV mass. We hypothesized that LA volumes would be increased with a decrease in atrial function in patients with HCM because of various pathophysiologic aspects of HCM, including myocardial fibrosis contributing to coexistent atrial myopathy.
Methods
The study was approved by human research ethics committees at Westmead Hospital and Royal Prince Alfred Hospital (Sydney, Australia). One hundred five participants constituted the study group: 35 patients with HCM (from the HCM clinic at Royal Prince Alfred Hospital) in New York Heart Association class I or II; 35 patients with HT matched for age, gender, and LV mass; and 35 normal controls. Patients with HCM had echocardiographic LV wall thicknesses > 13 mm in the absence of systemic HT, with LVOT obstructions in 17%. Patients were excluded if they had myectomy or alcohol septal ablation (n = 6), were pacemaker dependent (n = 11), or were in atrial fibrillation or had paroxysmal atrial fibrillation (n = 12). Twelve patients with HCM (34%) were not on any medications, 7 (20%) were on calcium antagonists, 15 (43%) were on β-blockers, and 2 (6%) were receiving both.
The HT group had documented blood pressure recordings > 140/90 mm Hg and were recruited from cardiology and renal departments and from the community. The duration and level of documented blood pressure were corroborated from patient records. Patients with more than mild valvular regurgitation or stenosis, histories of atrial arrhythmias, ejection fractions < 50%, previous cardiac surgery, or implanted devices were excluded. In the HT group, 8 patients (23%) were untreated, 9 (26%) were on calcium antagonists, 9 (26%) were on β-blockers, 1 (3%) was receiving both, 13 (37%) were on angiotensin-converting enzyme inhibitors, 13 (37%) were on angiotensin receptor blockers, and 8 (23%) were on diuretics. All recruited patients remained on their regular medications as determined by their treating physicians.
Patients with HCM were matched for the presence of diabetes mellitus and coronary artery disease to the HT group. In those patients without known ischemic heart disease, coronary artery disease was excluded by careful histories and electrocardiographic and echocardiographic evidence of previous infarctions.
Standard Transthoracic Echocardiography
Comprehensive echocardiography was performed according to established clinical laboratory practice using commercially available machines (Vivid 5 and 7; GE Vingmed Ultrasound AS, Horten, Norway) and offline measuring station EchoPAC (GE Vingmed Ultrasound AS) and Philips iE 33 (Philips Medical Systems, Eindhoven, The Netherlands) using harmonic 3.5-MHz variable-frequency phased-array transducers. LA diameter and LV wall thickness were measured by M-mode echocardiography. Biplane LV end-diastolic and end-systolic volumes were determined using the method of discs; the area-length method recommended by the American Society of Echocardiography was used to determine LV mass. LV volumes and LV mass were indexed to body surface area. Mitral regurgitation was graded qualitatively using color flow jet area, jet density, and contour using continuous-wave Doppler according to American Society of Echocardiography guidelines.
LA Volumes and Mechanical Function
Maximal (Vol max ), minimal (Vol min ), and pre-“p” (Vol p ) LA volumes were measured from the apical 4-chamber and 2-chamber zoomed views using Simpson’s biplane method of discs from an average of 3 cardiac cycles ( Figure 1 ). The following LA phasic parameters were derived and indexed to body surface area:
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LA total emptying volume = Vol max − Vol min ;
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LA total emptying fraction = LA total emptying volume/Vol max ;
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LA passive emptying volume = Vol max − Vol p ;
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LA passive emptying fraction = LA passive emptying volume/Vol max ;
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LA active emptying volume = Vol p − Vol min ;
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LA active emptying fraction = LA active emptying volume/Vol p ; and
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LA conduit volume = LV stroke volume − (Vol max − Vol min ).
Atrial Function: Transmitral Flow and A′ Velocity
Transmitral peak E-wave and A-wave velocities and the velocity-time integral of the A wave were measured. Atrial fraction was estimated as A-wave velocity-time integral divided by the total velocity-time integral of mitral inflow. Early diastolic E′ velocity and late diastolic A′ velocity were estimated using tissue Doppler. All parameters were measured as an average of 3 beats.
LV Diastolic Function
Mitral inflow peak E velocity, peak A velocity, E/A ratio, and deceleration time (DT) and isovolumic relaxation time were measured.
E′ velocity using tissue Doppler was measured from the septal and lateral annulus, and the E/E′ ratio was calculated. Grades of diastolic dysfunction were categorized as normal (grade 0), impaired relaxation (grade 1), pseudonormal (grade 2), and restrictive (grade 3) on the basis of previously published criteria. Grade 0 was defined as DT > 140 ms, E/A ratio > 1, and septal E/E′ ratio < 8 and grade 1 as DT > 140 ms, E/A ratio < 0.75, and E/E′ ratio < 8. Grade 2 was defined as DT > 140, E/A ratio > 1 and < 1.5, E/E′ ratio > 15, and systolic/diastolic pulmonary vein ratio < 1. Grade 3 was defined as E/A ratio > 1.5, DT < 140 ms, systolic/diastolic pulmonary vein ratio < 1, and E/E′ ratio >15.
Real-Time Three-Dimensional Echocardiography
Real-time three-dimensional (3D) echocardiography was performed in a subgroup of 33 patients (HCM, n = 20; HT, n = 11). Full-volume real-time 3D echocardiographic images were obtained at end-expiration from an apical window similar to two-dimensional (2D) images, over 3 cardiac cycles, using a 3D matrix-array transducer (Phillips iE33; Philips Medical Systems). Offline software (4D LV Cardio-View; TomTec Imaging, Munich, Germany) was used for quantifying 3D LA and LV volumes and LV ejection fraction, with measurements from 8 planes. Three-dimensional LV mass was measured as previously described. Figure 2 shows an example of measuring LA volumes in 3 dimensions.
Observer Agreement
In 10 randomly selected studies from the HT and HCM groups, two readers independently measured 2D LA Vol max and Vol min using Simpson’s biplane method of discs. Three-dimensional LA volumes were measured using TomTec offline software. One observer remeasured the same 20 studies at a separate time to determine intraobserver agreement from the baseline studies.
Statistical Analysis
All values are expressed as mean ± SD. Linear regression analysis was used to analyze the differences between the HT, HCM, and control groups, adjusting for body mass index. The differences between 2D and 3D echocardiography were analyzed using a paired Student’s t test. Categorical data were compared using χ 2 or Fisher’s exact tests as appropriate. The correlation between two variables was assessed using Pearson’s rank correlation coefficient. Univariate and multivariate regression analysis was used to examine independent predictors of increased LA volume in both groups. Bland-Altman analysis was used to compare 2D and 3D echocardiographically derived LA Vol max and LV mass and the observer variability of 2D and 3D LA volumes. Data were analyzed using SPSS version 15 (SPSS, Inc, Chicago, IL).
Results
Clinical and Echocardiographic Findings
Clinical characteristics of the HT, HCM, and control groups are presented in Tables 1 and 2 . The HCM group had significantly lower systolic and diastolic blood pressures and heart rates despite similar use of β-blockers and calcium antagonists. The overall use of medication as well as of angiotensin-converting enzyme inhibitors and angiotensin II blockers were higher in the HT group ( P = .02 and P = .001, respectively). Patients with HCM were more symptomatic, with chest pain, shortness of breath, and syncope.
| HCM | HT | Controls | |
|---|---|---|---|
| Variable | (n = 35) | (n = 35) | (n = 35) |
| Age (y) | 51 ± 13 | 51 ± 14 | 51 ± 13 |
| Men | 60% | 60% | 60% |
| Systolic blood pressure (mm Hg) | 124 ± 16 † | 142 ± 15 ∗ | 120 ± 10 |
| Diastolic blood pressure (mm Hg) | 74 ± 10 † | 86 ± 13 ∗ | 75 ± 9 |
| Mean arterial pressure (mm Hg) | 90 ± 11 † | 105 ± 12 ∗ | 90 ± 8 |
| Heart rate (beats/min) | 61 ± 10 ∗ † | 73 ± 13 | 70 ± 13 |
| Body mass index (kg/m 2 ) | 27.7 ± 3.6 | 30.0 ± 5.0 ∗ | 25.3 ± 3.8 |
| Body surface area (m 2 ) | 1.9 ± 0.2 | 2.0 ± 0.2 ∗ | 1.8 ± 0.2 |
| History of coronary artery disease | 2.9% | 5.7% | 0% |
| Diabetes mellitus | 5.7% | 8.6% | 0% |
| Chest pain | 34% ∗ | 3% | 0% |
| Shortness of breath | 54% ∗ | 9% | 0% |
| Syncope | 11% | — | 0% |
| β-blockers | 43% | 26% | — |
| Calcium antagonists | 20% | 26% | — |
| Variable | n |
|---|---|
| New York Heart Association functional class | |
| I | 32 |
| II | 3 |
| Distribution of hypertrophy | |
| Asymmetric | 29 |
| Symmetric | 4 |
| Apical | 2 |
| Mitral regurgitation | |
| Trivial or none | 9 |
| Mild | 21 |
| Moderate | 5 |
| Obstructive HCM (LV outflow tract gradient > 30 mm Hg) | 5 |
LA Size and Phasic Volumes
LA diameter and indexed LA Vol max , Vol min , Vol p were significantly increased in the HCM group ( Table 3 ). The indexed passive emptying volume was increased in the HCM group with a decrease in conduit volume; there was no difference in active emptying volume between the HCM and HT groups. The total, active and passive emptying fractions were significantly reduced in the HCM group ( Table 3 , Figure 3 ).
| HCM | HT | Controls | |
|---|---|---|---|
| Variable | (n = 35) | (n = 35) | (n = 35) |
| Ventricular septal thickness (mm) | 18.9 ± 4.3 ∗ † | 12.0 ± 2.2 | 9.6 ± 1.7 |
| Posterior wall thickness (mm) | 11.6 ± 2.2 ∗ | 11.8 ± 2.1 ∗ | 9.7 ± 2.1 |
| Diastolic pattern | |||
| Grade 0 (normal) | 14 (40%) † | 23 (65%) | 23 (66%) |
| Grade 1 (impaired relaxation) | 8 (23%) ∗ | 10 (29%) ∗ | 12 (34%) |
| Grade 2 (pseudonormal) | 13 (37%) ∗ † | 2 (6%) | 0 |
| Peak E (m/s) | 0.78 ± 0.21 | 0.73 ± 0.13 | 0.69 ± 0.13 |
| Peak A (m/s) | 0.63 ± 0.26 | 0.70 ± 0.18 | 0.61 ± 0.16 |
| E/A ratio | 1.4 ± 0.6 † | 1.1 ± 0.3 | 1.2 ± 0.4 |
| DT (ms) | 244 ± 59 ∗ | 222 ± 53 | 213 ± 43 |
| A velocity-time integral (cm) | 7.9 ± 3.3 | 7.9 ± 2.2 | 7.7 ± 2.1 |
| Isovolumic relaxation time (ms) | 119 ± 26 ∗ † | 97 ± 18 | 91 ± 14 |
| Septal E′ (m/s) | 5.2 ± 2.0 ∗ † | 7.2 ± 1.8 ∗ | 8.8 ± 3.4 |
| Septal A′ (m/s) | 8.0 ± 2.4 ∗ † | 9.9 ± 1.8 | 9.7 ± 2.1 |
| Septal E/E′ ratio | 17.9 ± 10.2 ∗ † | 10.6 ± 3.4 | 9.0 ± 3.2 |
| Lateral E/E′ ratio | 11.7 ± 8.6 ∗ | 8.8 ± 3.4 | 6.1 ± 2.0 |
| LA M-mode dimension (mm) | 44.7 ± 8.1 ∗ † | 40.7 ± 5.5 | 37.7 ± 4.0 |
| Atrial fraction (%) | 31.4 ± 10.0 ∗ † | 37.7 ± 8.2 | 39.6 ± 8.6 |
| LA ejection force (kdynes) | 6.2 ± 5.0 | 6.7 ± 3.5 | 4.8 ± 2.8 |
| LV end-diastolic volume (ml) | 80.1 ± 23.7 | 98.9 ± 31 | 85.9 ± 20.2 |
| LV end-systolic volume (ml) | 28.7± 10.4 | 35 ± 14 | 33.1 ± 8.6 |
| LV ejection fraction (%) | 65 ± 7 | 65 ± 7 | 61.3 ± 6.1 |
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