Background
The aim of this study was to test the hypothesis that patients with reverse-remodeled dilated cardiomyopathy (DCM), whose ejection fractions (EFs) were normalized after optimal pharmacologic therapy, had subclinical myocardial dysfunction.
Methods
Thirty-two patients with reverse-remodeled DCM, defined as having an initial EF ≤ 35%, which then recovered to ≥50% after optimal pharmacologic therapy, and 11 normal controls with preserved EFs were retrospectively studied. Averaged peak systolic and early diastolic radial, circumferential, and longitudinal speckle-tracking strain rates were assessed from an 18-segment left ventricular model. Similarly, averaged peak systolic radial, circumferential, and longitudinal speckle-tracking strain was obtained.
Results
Peak systolic and early diastolic longitudinal strain rates, peak systolic and early diastolic circumferential strain rates, and peak circumferential and longitudinal strain in patients with reverse-remodeled DCM were significantly lower than those in normal controls, but peak systolic and early diastolic radial strain rates and peak radial strain in patients with reverse-remodeled DCM were similar to those in normal controls. Isometric handgrip stress testing showed a significant decrease in EF from 56 ± 5% to 51 ± 5% ( P < .001). Of note, the increase of afterload resulting from isometric handgrip stress testing was associated with a decrease in peak systolic circumferential and longitudinal strain rates and peak circumferential strain in patients with reverse-remodeled DCM.
Conclusions
The circumferential and longitudinal myocardial function of patients with reverse-remodeled DCM is lower compared with that of normal controls with preserved EFs. Furthermore, the increase in afterload was associated with the decrease in circumferential and longitudinal myocardial systolic function. These findings suggest that in treated patients with DCM with reverse remodeling, left ventricular mechanics may not be normal, even when EFs are normal.
Dilated cardiomyopathy (DCM), characterized by dilated ventricles and diminished systolic function, is usually regarded as having a poor prognosis. According to early reports, survival was 70% to 75% at 1 year and 50% at 5 years. Current pharmacologic therapy, however, including the use of β-blockers, vasodilators, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, has led to significant improvement in the survival and control of symptoms of patients with DCM. Furthermore, marked improvements in left ventricular (LV) systolic function have been reported in 20% to 45% of patients with DCM. The improvement of myocyte Ca 2+ handling or the restoration of the response of down-regulated β-adrenergic receptors to sympathetic activation may play a role in normalizing in patients with DCM. However, it remains unknown whether regional myocardial function is also normalized in patients with DCM, even when LV ejection fraction (EF) has been normalized after optimal pharmacologic therapy. Subclinical LV dysfunction may be observed at rest and more often during exercise in patients with preserved EFs. The relationship between LV dysfunction induced by exercise and contractile function constitutes an intriguing problem. In fact, it has been demonstrated that an abnormal EF response to exercise cannot be equated with the presence of abnormal myocardial contractile reserve, and defective inotropic recruitment has been shown to play an important role in determining an abnormal LV response to exercise despite a normal inotropic reserve.
Accordingly, our objective was to test the hypothesis that patients with reverse-remodeled DCM had subclinical myocardial dysfunction as assessed in terms of two-dimensional speckle-tracking strain and strain rates, regardless of the normalization of EF after optimal pharmacologic therapy. We also assessed this subclinical myocardial dysfunction in terms of isometric handgrip and low-dose dobutamine stress test results.
Methods
Study Population
The study group retrospectively consisted of 34 patients with reverse-remodeled DCM between April 2005 and March 2011. Patients were eligible on the basis of the following inclusion criteria: (1) diagnosis of DCM, supported by endomyocardial biopsy findings, and (2) the presence of initial LV systolic dysfunction, defined as an EF ≤ 35%, and of recovered systolic function, defined as an EF ≥ 50% after optimal pharmacologic therapy. We excluded patients with (1) coronary artery disease, defined as a single coronary artery stenosis of >75% of a major epicardial vessel or a history of myocardial infarction; (2) other known causes of cardiomyopathy; (3) uncontrolled hypertension despite medical therapy; (4) significant valvular heart disease; (5) atrial fibrillation; and (6) left or right bundle branch block. All patients underwent coronary angiography, and no patients had coronary artery stenosis of >75% of a major epicardial vessel. Two initially eligible patients (5%) were excluded from all subsequent analyses because of suboptimal images from poor echocardiographic windows. As a result, the patient study group consisted of 32 patients, six women and 26 men ( Table 1 ). The group mean age was 56 ± 13 years, and the mean EF was 56 ± 5% (all ≥50%). Normal controls were randomly taken from our database to have a similar EF distribution. Thus, the normal control group consisted of 11 subjects (two women and nine men; mean age 52 ± 12 years; mean EF, 58 ± 4%) with no histories of cardiovascular disease and completely normal electrocardiographic findings as well as two-dimensional and Doppler echocardiographic results. Indication for echocardiography were as follows: nine normal volunteers (82%) and two subjects with atypical chest pain (18%). Written informed consent was obtained from all subjects.
| Variable | Normal controls ( n = 11) | Patients with reverse-remodeled DCM ( n = 32) | P |
|---|---|---|---|
| Age (y) | 52 ± 12 | 56 ± 13 | .33 |
| Men/women | 9/2 | 26/6 | 1.00 |
| Systolic blood pressure (mm Hg) | 113 ± 9 | 106 ± 15 | .25 |
| Diastolic blood pressure (mm Hg) | 66 ± 11 | 59 ± 11 | .06 |
| Heart rate (beats/min) | 66 ± 6 | 65 ± 9 | .62 |
| Medications | |||
| β-blockers | 0 (0%) | 31 (97%) | <.001 |
| ACE inhibitors/ARBs | 0 (0%) | 32 (100%) | <.001 |
| Statins | 0 (0%) | 10 (35%) | <.001 |
| Concomitant diseases | |||
| Systemic hypertension | 0 (0%) | 12 (37%) | <.001 |
| Dyslipidemia | 0 (0%) | 10 (31%) | <.001 |
| Diabetes mellitus | 0 (0%) | 6 (18%) | <.001 |
| EF (%) | 58 ± 4 | 56 ± 5 | .25 |
| E/A ratio | 1.00 ± 0.46 | 0.88 ± 0.34 | .04 |
| E′ (cm/sec) | 7.12 ± 2.15 | 7.01 ± 2.78 | .90 |
| E/E′ ratio | 9.96 ± 1.48 | 9.77 ± 3.56 | .86 |
| LV mass/volume ratio | 2.28 ± 0.25 | 2.56 ± 0.49 | .19 |
| ε-circ (%) | 21.3 ± 3.57 | 16.8 ± 3.09 | <.001 |
| ε-rad (%) | 37.3 ± 12.2 | 39.9 ± 11.2 | .52 |
| ε-long (%) | 18.8 ± 2.71 | 16.4 ± 2.88 | .02 |
| SSRcirc (sec −1 ) | 1.53 ± 0.32 | 1.31 ± 0.28 | .01 |
| SSRrad (sec −1 ) | 1.61 ± 0.35 | 1.61 ± 0.37 | .98 |
| SSRlong (sec −1 ) | 1.22 ± 0.28 | 1.00 ± 0.16 | <.001 |
| ESRcirc (sec −1 ) | 1.77 ± 0.39 | 1.31 ± 0.42 | .003 |
| ESRrad (sec −1 ) | 1.78 ± 0.41 | 1.69 ± 0.50 | .62 |
| ESRlong (sec −1 ) | 1.54 ± 0.24 | 1.25 ± 0.29 | .005 |
Echocardiography
All echocardiographic studies were performed using a commercially available echocardiographic system (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway). Digital routine grayscale two-dimensional cine loops from three consecutive heartbeats were obtained at end-expiratory apnea from standard apical views (four chamber, two chamber, and long axis) and standard LV short-axis views (basal, mid, and apical) at depths of 11 to 20 cm (mean, 16 ± 3 cm). Frame rates were 45 to 90 Hz (mean, 60 ± 10 Hz) for grayscale imaging. Sector width was optimized to allow complete myocardial visualization while maximizing the frame rate. The images were then exported to a personal computer and analyzed offline with customized software. LV volumes and EF were assessed by means of the biplane Simpson’s rule using manual tracing of digital images. LV mass was calculated using the formula proposed by Devereux et al, and the LV mass/volume ratio was determined to estimate LV wall stress. The pulsed-wave Doppler–derived transmitral velocity and digital color tissue Doppler–derived mitral annular velocity were obtained from the apical four-chamber view for assessment of diastolic function. The early diastolic (E) and atrial (A) wave velocities, the E/A ratio, and the E-wave deceleration time were measured using pulsed-wave Doppler recording. Spectral pulsed-wave Doppler–derived early diastolic velocity (E′) was obtained from the septal mitral annulus, and the E/E′ ratio was calculated to obtain an estimate of LV filling pressure. Digital data were transferred to dedicated offline software (EchoPAC version BTO8; GE Vingmed Ultrasound AS) for subsequent offline analysis.
Speckle-Tracking Strain Rate Analysis
The speckle-tracking strain rate was assessed for each subject with the aid of three different types of speckle tracking using offline software. Radial and circumferential strain rates were assessed from basal, mid, and apical LV short-axis views, and the longitudinal strain rate was assessed from the basal, mid, and apical levels in apical four-chamber, two-chamber, and long-axis views. The interobserver and intraobserver variability for each speckle-tracking strain rate was expressed as the absolute difference between the measurements divided by their mean value obtained from 10 randomly selected subjects in alphabetical order. The respective interobserver and intraobserver variability values were 10 ± 10% and 11 ± 14% for peak systolic radial strain rate (SSRrad), 13 ± 8% and 14 ± 11% for peak early diastolic radial strain rate (ESRrad), 13 ± 10% and 15 ± 11% for peak systolic circumferential strain rate (SSRcirc), 10 ± 10% and 11 ± 14% for peak early diastolic circumferential strain rate (ESRcirc), 15 ± 11% for peak systolic longitudinal strain rate (SSRlong), 13 ± 10% and 15 ± 11% for peak early diastolic longitudinal strain rate (ESRlong), 9 ± 8% and 9 ± 7% for peak radial strain (ε-rad), 9 ± 7% and 10 ± 6% for peak circumferential strain (ε-circ), and 9 ± 6% and 9 ± 8% for peak longitudinal strain (ε-long).
Radial and Circumferential Speckle-Tracking Strain Rate
A circular region of interest traced the endocardium at end-systole using a point-and-click approach. A second, larger concentric circle was then automatically generated near the epicardium and manually adjusted or manually traced. Special care was taken to fine-tune the region of interest, using visual assessment during cine loop playback to ensure that segments were tracked appropriately. Each LV image was then divided into six standard segments, and time–strain rate curves were generated from each segment ( Figure 1 ). Averaged SSRrad, ESRrad, SSRcirc, and ESRcirc strain rates were obtained from 18 LV segments. Similarly, averaged ε-rad and ε-circ were obtained from 18 LV segments.
Longitudinal Speckle-Tracking Strain Rate
A region of interest was traced at end-diastole in each three apical view using a point-and-click approach. A second, larger region of interest was then generated near the epicardium and manually adjusted. Special care was taken to fine-tune the region of interest, using visual assessment during cine loop playback to ensure that segments were tracked appropriately. Each apical image was then divided into six standard segments (at the basal, mid, and apical levels), and six corresponding time–strain rate curves were generated ( Figure 1 ). Averaged SSRlong and ESRlong were obtained from 18 LV segments. Similarly, averaged ε-long was obtained from 18 LV segments.
Stress Echocardiography
Echocardiography was administered to all patients while they underwent both the isometric handgrip stress and low-dose dobutamine stress tests.
Isometric Handgrip Stress Echocardiography
Maximum handgrip strength was determined for each patient by squeezing of the handgrip dynamometer with maximal voluntary strength. Measurements were then obtained after performing handgrip isometric exercise at 30% of the patient’s maximum grip strength for 3 to 5 min and while the handgrip was maintained as long as needed to acquire all echocardiographic images. Every effort was made to minimize possible alterations in the preload. Blood pressure and heart rate were measured at baseline and during handgrip isometric exercise.
Dobutamine Stress Echocardiography
Dobutamine was infused intravenously for 5 min at doses of 5 and 10 μg/kg/min, which are considered low doses. A three-lead electrocardiogram was used for continuous monitoring, and a 12-lead electrocardiogram was recorded at the end of each stage. Blood pressure and heart rate were obtained at rest and at the end of each stage. End points of the study included severe hemodynamic decompensation, significant ventricular or supraventricular arrhythmia, angina associated with electrocardiographic changes, new wall motion abnormalities in at least two segments, and achievement of 85% of the maximum age-predicted heart rate or completion of the protocol. Echocardiography was performed at rest and at the end of each stage.
Statistical Analysis
All group data were compared using two-tailed Student’s t tests for paired and unpaired data and are presented as mean ± SD. Proportional differences were evaluated using Fisher’s exact tests or χ 2 tests as appropriate. Correlation analysis was performed by means of linear regression, and results are expressed as Pearson’s correlation coefficients. For all tests, P values <.05 were considered statistically significant. All analyses were performed using SPSS version 15.0 (SPSS, Inc., Chicago, IL).
Results
The study group consisted of 32 patients for whom complete data sets consisting of conventional echocardiographic and speckle-tracking strain and strain rate data were available, and 11 normal volunteers with baseline and with isometric handgrip stress echocardiographic data. Peak systolic radial, circumferential, and longitudinal speckle-tracking strain and strain rate measurements were obtainable from 95% and 93%, 94% and 92%, and 95% and 94%, respectively, and their early diastolic counterparts from 93%, 93%, and 91%, respectively, of 1,548 attempted segments from 43 subjects (32 patients with baseline, isometric handgrip, and dobutamine stress echocardiographic data and 11 normal controls with baseline and isometric handgrip data). If not all segments of a given subject could be assessed, only assessable segments were included for speckle-tracking strain rate analysis.
Comparison of Baseline Echocardiographic Parameters for Patients with Reverse-Remodeled DCM and Normal Controls with Preserved EFs
The baseline clinical and standard echocardiographic characteristics of the 32 patients and 11 normal controls are summarized in Table 1 . All patients were treated with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists. Beta-blockers were added to the regimen for 31 patients (97%). E′ and the E/E′ ratio were similar between two groups, but the E/A ratios of patients with reverse-remodeled DCM were significantly lower than those of normal controls with preserved EFs. The ε-long and SSRlong values in patients with reverse-remodeled DCM were significantly lower than those in normal controls with preserved EFs (16.4 ± 2.88% vs 20.0 ± 2.89%, P < .001 vs controls, and 1.00 ± 0.16 vs 1.24 ± 0.27 sec −1 , P < .001 vs controls). Furthermore, ε-circ and SSRcirc in patients with reverse-remodeled DCM were significantly lower than those in normal controls with preserved EFs (16.8 ± 3.09% vs 22.0 ± 3.67%, P < .001 vs controls, and 1.31 ± 0.28 vs 1.53 ± 0.31 sec −1 , P = .01 vs controls). ESRlong and ESRcirc in patients with reverse-remodeled DCM were also significantly lower than those in controls (1.25 ± 0.29 vs 1.58 ± 0.23 sec −1 and 1.31 ± 0.42 vs 1.80 ± 0.37 sec −1 , respectively, P = .001 vs controls). However, ε-rad, SSRrad, and ESRrad in patients with reverse-remodeled DCM were similar to those in normal controls.
Effects of Handgrip Stress on Regional Myocardial Function of Normal Controls with Preserved EFs
Systolic blood pressures and heart rates of normal controls significantly increased with the handgrip stress test, but no significant changes were observed in other parameters, including EF and strain rate and strain indices ( Table 2 ).
| Variable | Baseline | Handgrip stress | P |
|---|---|---|---|
| Systolic blood pressure (mm Hg) | 113 ± 9 | 130 ± 13 | .01 |
| Diastolic blood pressure (mm Hg) | 66 ± 11 | 76 ± 14 | .25 |
| Heart rate (beats/min) | 66 ± 6 | 73 ± 7 | .05 |
| EF (%) | 58 ± 4 | 59 ± 4 | .67 |
| EDV (mL) | 80 ± 19 | 82 ± 17 | .78 |
| ESV (mL) | 35 ± 11 | 35 ± 8 | .92 |
| E/A ratio | 1.00 ± 0.46 | 0.99 ± 0.43 | .98 |
| E′ (cm/sec) | 7.12 ± 2.15 | 7.06 ± 2.74 | .95 |
| E/E′ ratio | 9.96 ± 1.48 | 10.3 ± 2.1 | .64 |
| ε-circ (%) | 21.3 ± 3.6 | 21.2 ± 5.0 | .94 |
| ε-rad (%) | 37.3 ± 12.2 | 41.4 ± 17.8 | .53 |
| ε-long (%) | 18.8 ± 2.7 | 20.0 ± 3.7 | .40 |
| SSRcirc (sec −1 ) | 1.53 ± 0.32 | 1.71 ± 0.41 | .26 |
| SSRrad (sec −1 ) | 1.61 ± 0.35 | 1.70 ± 0.25 | .46 |
| SSRlong (sec −1 ) | 1.22 ± 0.28 | 1.18 ± 0.28 | .75 |
| ESRcirc (sec −1 ) | 1.77 ± 0.39 | 1.86 ± 0.30 | .53 |
| ESRrad (sec −1 ) | 1.78 ± 0.41 | 1.87 ± 0.43 | .59 |
| ESRlong (sec −1 ) | 1.54 ± 0.24 | 1.55 ± 0.29 | .96 |
Effects of Handgrip Stress on Regional Myocardial Systolic Function of Patients with Reverse-Remodeled DCM
Systolic and diastolic blood pressures and heart rates of patients with reverse-remodeled DCM significantly increased with the handgrip stress test (106 ± 15 vs 126 ± 18 mm Hg, 59 ± 11 vs 69 ± 12 mm Hg, and 65 ± 9 vs 72 ± 12 beats/min, respectively, P < .001 vs baseline), but no significant changes were observed in global diastolic function (E/A ratio, 0.88 ± 0.34 vs 0.81 ± 0.33; E′, 7.01 ± 2.78 vs 7.13 ± 2.76) and E/E′ ratio (9.77 ± 3.56 vs 9.35 ± 3.55). End-systolic volume significantly increased from 37 ± 10 to 41 ± 10 mL ( P = .0003), and EF significantly decreased from 56 ± 5% to 51 ± 5% ( P < .001) with the handgrip stress test ( Table 3 ). Of note is that SSRcirc, SSRlong, and ε-circ significantly decreased with the handgrip stress test from 1.31 ± 0.28 to 1.10 ± 0.18 sec −1 , from 1.00 ± 0.16 to 0.90 ± 0.17 sec −1 (both P values <.05), and from 16.8 ± 3.1% to 14.1 ± 3.4% ( P = .001), respectively ( Table 3 ). On the other hand, SSRrad did not change significantly, remaining virtually unchanged at 1.61 ± 0.37 sec −1 and 1.58 ± 0.37 sec −1 ( Table 3 ).
