Background
Hypertrophic cardiomyopathy (HCM) represents a generalized myopathic process affecting both ventricular and atrial myocardium. We aimed to assess left atrial (LA) function by two-dimensional speckle tracking echocardiography and its relation with left ventricular (LV) function and clinical status in patients with HCM.
Methods
We prospectively enrolled 37 consecutive patients with HCM and 37 normal subjects with similar age and gender distribution. Longitudinal LV strain (ϵ) and LA ϵ and strain rate (Sr) parameters (systolic, early diastolic, and late diastolic during atrial contraction) were assessed.
Results
Peak LAϵ and LA Sr parameters were significantly lower in patients compared with controls ( P ≤ . 001 for all). In patients, all LA function parameters correlated with LVϵ ( P < . 003 for all). Indexed LA volume, LA function parameters, and mitral regurgitation degree were the main correlates of New York Heart Association class; late diastolic strain rate during atrial contraction was the only independent predictor of symptomatic status.
Conclusion
In patients with HCM, LA function is significantly reduced and related to LV dysfunction. Moreover, LA booster pump function emerged as an independent correlate of heart failure symptoms in this setting.
Hypertrophic cardiomyopathy (HCM) is characterized by a generalized myopathic process affecting both ventricular and atrial myocardium. Left ventricular (LV) dysfunction and remodeling of the left atrium (LA) are common features of HCM. Moreover, LA dilation has proved to be a powerful determinant of exercise capacity and adverse outcome in this setting.
In patients with symptomatic HCM, exertional dyspnea is a common symptom. LA function plays a central role in maintaining optimal cardiac output despite impaired LV relaxation and reduced LV compliance. It has been demonstrated that the Frank-Starling mechanism is also operative in the LA and that LA output increases as atrial diameter increases, which contributes to maintaining a normal stroke volume. LV diastolic dysfunction, elevated filling pressure, LV hypertrophy, LV outflow tract obstruction, mitral regurgitation, and intrinsic atrial myopathy are all potential contributors to ongoing LA remodeling. Increased LA volume may be accompanied by a progressive impairment in LA function, and both may precede symptom development and adversely affect prognosis. The role of LA dysfunction in the symptomatic status of patients with HCM has not been addressed.
There is a close interdependence between LV and LA function. LA reservoir function is influenced by LV contraction through the descent of LV base during systole, LA relaxation, and stiffness; LA conduit function is dependent on LV relaxation and preload; and LA booster pump function is influenced by LV compliance, LV filling pressures, and intrinsic LA contractility. Moreover, despite the existing theory of a generalized myopathic process affecting both ventricular and atrial myocardium, the relationship between LA myocardial function and the degree of LV dysfunction in patients with HCM has not been examined.
Both LV function and LA function (reservoir, conduit, and active contractile functions) can be adequately examined by two-dimensional speckle-tracking echocardiography (STE). Strain imaging overcomes the main drawbacks of tissue Doppler-derived myocardial velocities and thus provides more accurate quantification of regional myocardial function.
In the present study, we hypothesized that 1) LV longitudinal dysfunction is accompanied by an impairment of LA longitudinal function and that 2) heart failure symptoms are related in part to LA dysfunction in patients with HCM.
Materials and Methods
Study Population
For enrollment, we prospectively screened consecutive patients who had been referred to our echocardiography laboratory and who met the diagnostic criteria for HCM: M-mode and two-dimensional echocardiographic evidence of a hypertrophied (diastolic wall thickness ≥ 15 mm), nondilated LV in the absence of exercise training history and cardiac or systemic conditions capable of inducing that magnitude of hypertrophy. Patients with a poor acoustic window, patients who were technically unsuitable for STE analysis, and patients with non-sinus rhythm were excluded. The final study population consisted of 37 patients. The following clinical data were collected: age, gender, history of smoking, hypertension (defined as history of hypertension requiring medical therapy), diabetes mellitus, and hypercholesterolemia. The clinical status was defined according to the New York Heart Association (NYHA) classification. Information regarding current medication was also obtained. Thirty-seven healthy volunteers with similar age and gender distribution served as a control group. They had no evidence of heart disease by physical examination, 12-lead electrocardiogram, and echocardiography and were taking no medication. All subjects gave their informed consent to participate in the study.
Echocardiographic Study
A commercially available ultrasound machine (Vivid 7, General Electric Medical Systems, Horten, Norway) equipped with an M4S probe was used for all echocardiographic examinations. Standard echocardiographic views were obtained using second-harmonic imaging with frequency, depth, and sector width adjusted for frame-rate optimization (between 60-100 fps). Image settings and frame-rates were kept similar for LV four-chamber, two-chamber, and long-axis apical views, which were recorded immediately one after another. For LA size measurements (area and volume) and deformation analysis, a conventional apical four-chamber view was recorded with attention to LA cavity optimization and wall definition. The LA appendage and the confluence of the pulmonary veins were excluded from the measurements. From the apical four-chamber view, the pre-atrial contraction LA volume and the minimal and maximal LA volumes were measured using the area-length method. LA active emptying fraction, LA expansion index, and LA passive emptying fraction were calculated as previously described. LV volumes and ejection fraction were calculated using Simpson’s biplane method. LV mass was calculated by the equation of Devereux. All volumes and LV mass were normalized to body surface area. The maximal LA volume indexed to body surface area (LAVi) was used in further statistical analyses. Peak systolic (S) and peak early diastolic (E’) mitral annular velocities were obtained by pulse-wave tissue Doppler imaging from the apical four-chamber view using both the septal and the lateral sites. The average E’ was used to calculate the ratio of peak early-diastolic transmitral flow velocity E to E’, to estimate LV filling pressures. LV diastolic dysfunction was graded according to the American Society of Echocardiography/European Association of Echocardiography recommendations: grade I (impaired relaxation), grade II (pseudonormal filling pattern), and grade III (restrictive filling pattern). LV outflow tract gradient was measured by continuous-wave Doppler from the apical 5-chamber view. LV outflow tract obstruction was defined as a peak gradient > 30 mm Hg at rest or during Valsalva maneuver. Color Doppler echocardiography was used for the semiquantitative assessment of mitral regurgitation severity, as recommended.
Both two-dimensional and Doppler images were digitally stored as three consecutive cycles recorded during end-expiratory apnea. Data were analyzed offline using a commercially available software package (EchoPac PC version BT08; General Electric Medical Systems) by a single observer experienced in two-dimensional strain quantitation by STE.
Measurement of Left Ventricular Strain and Left Atrial Strain and Strain Rate Parameters
Analysis of LV strain by STE was performed on the four-chamber, two-chamber, and long-axis apical views, as previously described. Briefly, after manually tracing the LV endocardium, an automatically generated region of interest divided into six segments was provided for each view, which could be adjusted by contour position refinements and width tuning to fit the LV wall. LV segments with inadequate image quality were rejected by the software, leading to subject exclusion from further study. LV longitudinal strain was measurable from the apical four-chamber view in all patients. Global longitudinal peak systolic LV strain values, calculated using a 17-segmental model, were validated by the software in 30 patients. LV longitudinal strain rate (Sr) parameters (systolic Sr, early diastolic Sr, and late diastolic Sr) were also measured from the apical four-chamber view.
Analysis of LA strain and strain rate parameters by STE was performed on the same four-chamber view in which LA area and volume measurements were performed. Similar to STE-derived LV analysis, longitudinal global LA strain and strain rate parameters were assessed as the average of six segmental values. Peak LA strain (ϵ) and Sr (systolic [SSr], early diastolic [ESr], and late diastolic strain rate during atrial contraction [ASr]) were measured as LA function parameters: SSr for reservoir function, ESr for conduit function, and ASr for booster pump function.
Statistical Analysis
Measurements are presented as mean ± standard deviation. Variables were compared using Student t test, analysis of variance, or chi-square test when appropriate. The relationships between different parameters were assessed by correlation analysis: Pearson’s method for continuous, normally distributed variables and Spearman’s rho method for ordinal or continuous but skewed variables.
To assess the comparative accuracy of different echocardiography variables in identifying symptomatic patients with HCM, receiver operating characteristic curves and the respective area under the curve were calculated for every parameter related to NYHA class. Predictors of symptomatic status in patients with HCM were assessed using binary logistic analysis. Variables with a P < .15 in univariate analyses were included in the multivariable model. All statistical analyses were performed using SPSS 14.0 software for Windows (SPSS, Inc, Chicago, IL). A two-sided P value of .05 was considered significant. Measurement variability was assessed for LAϵ and Sr parameters in a randomly selected group of 15 patients with HCM. For interobserver variability, measurements were carried out by a second operator on previously acquired images. For intraobserver variability, two sets of measurements were carried out by the same operator, 1 month apart. Variability was calculated as the absolute differences between two measurements divided by the mean of the two measurements.
Results
Study Participants
Table 1 lists demographic and echocardiographic characteristics of the study population. There were no significant differences between patients and control subjects with respect to age, gender, body surface area, or heart rate ( P > .05 for all). LV outflow tract obstruction was present in 20 patients. Thirty-six patients had mitral regurgitation (grade 1 in 11 ; grade 2 in 12; grade 3 in 12; and grade 4 in 1). As expected, patients with HCM had higher indexed LV mass, LAVi, E/E’ ratio, and lower S-wave velocities at both lateral and septal sites compared with control subjects ( P < . 001, for all). LV global longitudinal function (LVϵ) was severely reduced in patients with HCM, despite the slightly higher LV ejection fraction. Twelve patients were asymptomatic (NYHA class I), and 25 patients were symptomatic (NYHA class II in 15, class III in 7, and class IV in 3).
| Controls (n = 37) | Asymptomatic patients (n = 12) | Symptomatic patients (n = 25) | P value | |
|---|---|---|---|---|
| Age (y) | 48 ± 12 | 46 ± 16 | 53 ± 15 | .30 |
| Men, n (%) | 16 (43) | 6 (50) | 12 (48) | .81 |
| Body mass index (kg/m 2 ) | 25 ± 3 | 25 ± 5 | 28 ± 5 ∗ | .04 |
| LV parameters | ||||
| LV mass index (g/m 2 ) | 87 ± 13 | 176 ± 42 ∗ | 193 ± 73 ∗ | <.001 |
| LV EDVi (mL/m 2 ) | 49 ± 10 | 47 ± 18 | 47 ± 15 | .84 |
| LV ESVi (mL/m 2 ) | 19 ± 4 | 16 ± 8 | 16 ± 6 | .31 |
| LV ejection fraction (%) | 62 ± 3 | 66 ± 8 | 65 ± 7 ∗ | .02 |
| Mitral E velocity (cm/s) | 79 ± 12 | 79 ± 16 | 78 ± 26 | .97 |
| Mitral A velocity (cm/s) | 56 ± 11 | 78 ± 24 ∗ | 72 ± 30 ∗ | .003 |
| Mitral E deceleration time (ms) | 168 ± 38 | 203 ± 63 | 213 ± 90 ∗ | .02 |
| Peak septal S velocity (cm/s) | 7.6 ± 1 | 6.2 ± 1.6 ∗ | 5.5 ± 1.4 ∗ | <.001 |
| Peak lateral S velocity (cm/s) | 9.9 ± 2.4 | 6.2 ± 1.7 | 6.2 ± 2.0 | <.001 |
| Peak septal E’ velocity (cm/s) | 11.0 ± 2.5 | 5.1 ± 1.8 ∗ | 4.9 ± 2.1 ∗ | <.001 |
| Peak lateral E’ velocity (cm/s) | 15.5 ± 4 | 5.6 ± 1.4 ∗ | 6.3 ± 2.2 ∗ | <.001 |
| Peak septal A’ velocity (cm/s) | 7.6 ± 1.6 | 7.1 ± 1.7 | 5.8 ± 2,2 ∗ | .002 |
| Peak lateral A’ velocity (cm/s) | 7.8 ± 1.9 | 8.8 ± 4.0 | 6.5 ± 2.9 | .05 |
| E/E’ ratio | 6.3 ± 1.5 | 14.9 ± 3.5 ∗ | 15.6 ± 6.6 ∗ | <.001 |
| LV ϵ (%) | −20.5 ± 2.7 | −13.8 ± 2.9 ∗ | −11.6 ± 3.8 ∗ | <.001 |
| LA parameters | ||||
| LAVi (mL/m 2 ) | 33 ± 8 | 49 ± 13 ∗ | 77 ± 39 ∗† | <.001 |
| LA ϵ (%) | 32.0 ± 8.5 | 20.2 ± 5.1 ∗ | 13.3 ± 5.6 ∗† | <.001 |
| LA SSr (s −1 ) | 1.3 ± 0.2 | 0.9 ± 0.2 ∗ | 0.6 ± 0.2 ∗† | <.001 |
| LA ESr (s −1 ) | −1.6 ± 0.5 | −0.7 ± 0.2 ∗ | −0.5 ± 0.1 ∗ | <.001 |
| LA ASr (s −1 ) | −1.6 ± 0.6 | −1.3 ± 0.4 ∗ | −0.7 ± 0.4 ∗† | <.001 |
| LV outflow tract obstruction, n (%) | – | 5 (42) | 15 (60) | .3 |
| Mitral regurgitation (1/2/3/4 degree) | – | 8/2/1/1 | 3/10/11/0 | .05 |
∗ P < .05 patients with HCM vs controls.
Left Atrial Function Parameters in Patients with Hypertrophic Cardiomyopathy
Left atrial strain and LA Sr (SSr, ESr, ASr) parameters were severely decreased in patients with HCM ( Table 1 ). LA function parameters (except for ESr) were significantly lower (LAϵ, 13.3 ± 5.6 vs. 20.2 ± 5.1%; SSr, 0.6 ± 0.2 vs. 0.9 ± 0.2 s −1 ; ASr, −0.7 ± 0.4 vs. −1.3 ± 0.4 s −1 , P < . 02 for all), and LAVi was significantly higher (77 ± 39 vs. 49 ± 13 mL/m 2 , P = .006) in symptomatic compared with asymptomatic patients with HCM ( Figure 1 ). There were no significant differences between asymptomatic and symptomatic patients with HCM with respect to age, gender, E/E’ ratio, S, E’, A’-wave velocities at both lateral and septal sites, LV ejection fraction, or LVϵ ( Table 1 ).
Left atrial strain (LA ϵ), systolic Sr (SSr), and late diastolic Sr (ASr) were significantly related to LAVi and to LV mass in patients with HCM. Early diastolic LA Sr (ESr) decreased with increasing age ( Table 2 ). There was a significant correlation between LA functional indices derived from volumetric changes and LA-derived strain parameters. LA expansion index correlated significantly with LA ϵ (r = 0.57, P < . 001) and SSr (r = 0.48, P = .003), LA passive emptying fraction correlated with ESr (r = −0.34, P = .04), and LA active emptying fraction correlated with ASr (r = −0.62, P < . 001).
| LA ϵ | SSr | ESr | ASr | |||||
|---|---|---|---|---|---|---|---|---|
| P | r | P | r | P | r | P | r | |
| Age | .70 | .47 | .03 | 0.36 | .48 | |||
| LVMi | .001 | −0.53 | .007 | −0.45 | .13 | .01 | 0.40 | |
| Mitral E velocity | .16 | .23 | .67 | .05 | ||||
| Mitral A velocity | .58 | .75 | .04 | 0.35 | .22 | |||
| Mitral E deceleration time | .47 | .87 | .04 | 0.34 | .51 | |||
| Peak septal S velocity | <.001 | 0.56 | .004 | 0.47 | .01 | −0.40 | .01 | −0.43 |
| Peak lateral S velocity | .31 | .15 | .81 | .21 | ||||
| Peak septal E’ velocity | .25 | .51 | .005 | −0.46 | .49 | |||
| Peak lateral E’ velocity | .78 | .61 | .36 | .79 | ||||
| Peak septal A’ velocity | <.001 | 0.72 | <.001 | 0.68 | .01 | −0.41 | <.001 | −0.77 |
| Peak lateral A’ velocity | <.001 | 0.66 | <.001 | 0.65 | .01 | −0.45 | <.001 | −0.82 |
| E/E’ ratio | .02 | −0.41 | .02 | −0.40 | .007 | 0.49 | .06 | |
| LV EF | .17 | .12 | .41 | .81 | ||||
| LV ϵ | <.001 | −0.79 | <.001 | −0.71 | .007 | 0.48 | .003 | 0.53 |
| LAVi | .002 | −0.51 | .008 | −0.44 | .17 | .003 | 0.48 | |
| MR degree | .04 | −0.33 | .16 | .07 | .02 | 0.36 | ||
Intraobserver variability was 4.1% ± 3.4% for LAϵ, 7.5% ± 6.4% for SSr, 8.1% ± 6.0% for ESr, and 6.4% ± 5.7% for ASr. Interobserver variability for the same parameters was 5.9% ± 4.5%, 8.1% ± 3.2%, 12.9% ± 8.4%, and 9.5% ± 7.8%, respectively.
Relationship of Left Atrial Function with Left Ventricular Systolic and Diastolic Function in Patients with Hypertrophic Cardiomyopathy
All atrial function parameters (LAϵ, SSr, ESr, and ASr) were significantly related to LV global longitudinal strain ( Figure 2 ). A similarly close correlation was found between LV longitudinal strain measured from the apical four-chamber view and LA function parameters (r = −0.72, P < . 001 for LAϵ; r = −0.62, P < . 001 for SSr; r = 0.45, P = .005 for ESr; and r = 0.48, P = .003 for ASr). Significant correlations were also found between LA function parameters and septal S, but not with lateral S. LV ejection fraction was not related to LAϵ, SSr, ESr, or ASr. Left atrial conduit function (ESr) and LA reservoir function (LAϵ and SSr), were related to E/E’ ratio, in contrast with LA booster pump function (ASr) ( Table 2 ). Only LA conduit function was related to LV early diastolic longitudinal Sr (r = −0.43, P = .01), whereas LA reservoir and LA booster pump functions were not ( P > .05 for both). LV late diastolic longitudinal Sr correlated with LAϵ (r = 0.46, P = .007), SSr (r = 0.42, P = .01), and ASr (r = −0.75, P < . 001). There were no significant correlations between LV diastolic dysfunction degree and LA function parameters ( P > .05 for all).
Indexed LA volume was related to indexed LV mass (r = 0.64, P < . 001) and LV longitudinal strain (r = 0.56, P = .001). Neither E/E’ ratio nor LV outflow tract gradient was related to LAVi ( P > .05 for both), whereas mitral regurgitation severity had only a weak correlation (r = 0.35, P = .03) with LA volume.
Correlates of New York Heart Association Class in Patients with Hypertrophic Cardiomyopathy
The main correlates of NYHA class in patients with HCM were LA function parameters (LAϵ, SSr, ESr and ASr), LAVi, and mitral regurgitation degree ( Table 3 ). LA function parameters were the only significant correlates of NYHA class by analysis of variance. LV mass, LV ejection fraction, S, E’, A’-wave velocities at both lateral and septal sites, and E/E’ ratio were not related to NYHA class. LV outflow tract obstruction was not significantly different between asymptomatic and symptomatic patients and did not correlate with symptomatic status. Moreover, the resting peak LV outflow tract gradient was not significantly different between asymptomatic and symptomatic patients with HCM (69 ± 39 vs 81 ± 35 mm Hg, P = .51). To comparatively assess the accuracy of LAVi and LA function parameters (LAϵ, SSr, ESr, and ASr) in identifying symptomatic patients with HCM, receiver operating characteristic curves and the corresponding area under the curve were calculated. The best result has been obtained for ASr (area under the curve: 0.83) with a cutoff of −0.92 s −1 for identifying symptomatic patients with HCM (sensitivity: 75%, specificity: 83%) ( Figure 3 ). The correlates of symptomatic status are displayed in Table 4 . At multivariable logistic regression analysis, ASr emerged as the only independent correlate of heart failure symptoms in our study population (odds ratio = 2.63; 95% confidence interval, 1.015-6.922, P = .04).
