The present study proposed to evaluate whether analysis of cardiac mechanics through speckle-tracking imaging is useful for risk stratification in asymptomatic patients with chronic primary mitral regurgitation (MR). We prospectively enrolled 67 patients (mean age 57 ± 18 years) and followed them over time. MR was mild in 20 patients (30%), moderate in 24 (36%), and severe in 23 (34%). After a mean time of 24.8 ± 17 months, 34 patients (51%) remained asymptomatic, whereas 33 (49%) developed events (19 underwent mitral valve surgery, 9 required hospitalization for acute heart failure, and 5 patients died). Compared to asymptomatic patients, those with events at baseline showed more severe MR, larger and spherical ventricles, diastolic dysfunction, and greater systolic pulmonary arterial pressure. Moreover, patients with events had decreased left atrial (LA) reservoir (p <0.001) and left ventricular (LV) untwisting rate (p <0.001). On univariate Cox regression analysis, effective regurgitant orifice area (p <0.001), vena contracta (p <0.001), systolic pulmonary arterial pressure (p = 0.003), LV end-systolic diameter (p <0.001), E/E′ ratio (p = 0.004), LA volume (p = 0.001), LA reservoir (p <0.001), and LV untwisting rate (p <0.001) were associated with an increased risk of events. On multivariate analysis, only LA reservoir (p = 0.013) and LV untwisting rate were independent predictors (p = 0.017) of outcome. Moreover, LA reservoir evaluation significantly improved (p = 0.013) risk stratification compared to recommended parameters. In conclusion, impaired cardiac mechanics is more closely associated than severity of MR with the occurrence of events in asymptomatic chronic primary MR.
Speckle-tracking echocardiography (STE) has been extensively aimed at early identification of subtle myocardial dysfunction in various cardiac diseases. Particularly, several studies have highlighted the incremental values of STE in a deeper evaluation of cardiac mechanics in patients with mitral regurgitation (MR). Mitral valve prolapse (MVP) is the main cause of chronic primary MR. The natural history of the disease is characterized by asymptomatic stages (A, B, C) of variable duration. Despite the absence of symptoms, cardiac remodeling affects the left atrium beyond the ventricle during these stages. However, according to current guidelines, left ventricular (LV) ejection fraction (EF), end-systolic diameter (ESD), systolic pulmonary arterial pressure (SPAP), and new onset of atrial fibrillation (AF) are the only parameters recommended to be monitored for an early surgery in asymptomatic patients. Nevertheless, in patients with chronic MR, both LVEF and ESD may be within the normal range for a long time; furthermore, AF often occurs when the atrial damage already is irreversible. We previously demonstrated that left atrial (LA) reservoir and LV untwisting are helpful parameters in unmasking incipient myocardial dysfunction in patients with MVP. In the present study, we aimed to evaluate whether the same indexes are predictors of prognosis and whether they provide an incremental value for assessing outcome beyond conventional evaluation.
Methods
Sixty-seven asymptomatic patients (37 men, mean age 57 ± 18 years) functioning at New York Heart Association Class I and affected by chronic primary MR but with normal systolic function, defined as an LVEF ≥60%, were prospectively enrolled. Patients were excluded for the following conditions: presence of another more-than-mild heart valve disease, SPAP at rest >50 mm Hg, diagnosis of heart failure, and/or permanent AF. Furthermore, patients with suspected ischemic heart disease were excluded after treadmill testing in all patients. A medical history was obtained for all participants, and each subject underwent a physical examination. Body surface area was calculated using the Du Bois formula. The local ethics research committee approved the protocol, and each subject signed an informed consent form. A Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway) equipped with a cardiac M4S transducer was used for baseline MR quantification and analysis of left-chamber mechanics.
Mitral valve prolapse was diagnosed when the coaptation line appeared 2 mm behind the annular plane using a parasternal long-axis view. The anatomy of the mitral valve apparatus was systematically evaluated to identify prolapsing scallops and/or the presence of a flail leaflet; transesophageal echocardiography was performed when appropriate. The severity of MR was assessed by effective regurgitant orifice area (EROA), calculated using the proximal isovelocity surface area method. Accordingly, MR was considered mild when the EROA was ≥0.10 and ≤0.19 cm 2 , moderate when the EROA was ≥0.20 and ≤0.39 cm 2 , and severe when the EROA was ≥0.40 cm 2 . Quantification of MR was completed by vena contracta (VC) measurement, taking into consideration a cut-off value of 0.7 cm for severe MR. The LV end-diastolic and end-systolic diameters and volumes were measured and indexed to body surface area, and EF was calculated using biplane Simpson method. End-diastolic relative wall thickness, LV mass index (g/m 2 ), and sphericity index were obtained to assess LV geometry. Indexed LA area and biplane volumes also were calculated. Mitral flow peak early ( E ) and late ( A ) diastolic filling velocities, E / A ratio, and deceleration time were measured as markers of diastolic function. In addition, spectral tissue Doppler imaging was used to obtain peak early diastolic mitral annulus velocity ( E ′) and E / E ′ ratio. The SPAP was calculated through tricuspid regurgitation, and right atrial pressure was added when appropriate.
Analysis of 2-dimensional (2D) strain was performed offline, as already shown, using semiautomatic tracking on cardiac images previously transferred to an EchoPac workstation (V.8.0.0, GE). LA function was studied from the apical 4- and 2-chamber views of the conventional 2D grayscale images during a brief breath-hold and with a stable electrocardiogram recording, according to the recommendation for evaluating cardiac mechanics. The LA endocardial border was manually traced, delineating a region of interest that consisted of 6 segments in apical 4-chamber view and 6 segments in apical 2-chamber view. Peak atrial longitudinal strain (reservoir), measured at the end of LV systole, was calculated by averaging values from all (12) LA segments and by separately averaging values observed in the 4- and 2-chamber views. Global longitudinal strain was obtained by automated function imaging for LV strain analysis, whereas global circumferential strain and global radial strain were calculated by estimating the average strain derived by myocardial tracking from each view. Ventricular twist (degrees), torsion (degrees), and untwisting rate (degree/s) also were assessed, as previously shown. Particularly, the opposite rotation after LV twist was defined as LV untwist, and the time derivative of LV untwist was defined as the LV untwisting rate (°/sec), that is, the early diastolic rotation rate, a surrogate marker of LV recoil.
Follow-up information was obtained every 6 months from interviews with patients, their relatives, or their physicians. Spontaneous information coming from the patient or family members was collected anytime. The predefined end points for assessing the outcome were the occurrence of symptoms (acute heart failure requiring hospitalization), mitral valve surgery (repair or replacement), or death during follow-up. We took the first experienced event as an end point with subsequent censoring. A clinical and not echocardiographic follow-up was established; therefore, each patient was free to undergo a new echocardiographic examination at institutions other than our hospital. At the end of follow-up (mean 24.8 ± 17 months, ranging from 10 days to 75.6 months), patients were divided into 2 groups according to the occurrence of events: group 0 (n = 34), including all patients who remained asymptomatic, and group 1 (n = 33), consisting of those who experienced one event during follow-up.
Data were analyzed using SPSS (V.17 for Windows; SPSS Inc., Chicago, Illinois). The data are expressed as mean ± standard deviation. Each variable was analyzed for normal distribution using the Kolmogorov–Smirnov test. One-way analysis of variance and post hoc Bonferroni testing were used to compare continuous variables between groups with different MR degree. Comparison of continuous variables between the 2 groups (with and without events) at the end of follow-up was performed using the Student t test for independent samples. Pearson and Spearman coefficients were used to test the correlation between continuous and categorical variables as appropriate. Univariate and multivariate Cox regression analyses were used to identify possible predictors of events. Receiver operating characteristic (ROC) curves were generated to identify the optimal cutoff for LA reservoir and LV untwisting rate. Kaplan–Meier event-free survival curves, according to LA reservoir and LV untwisting rate cut-off values identified by ROC analysis, were computed for predicting the occurrence of events; log-rank test was used to compare different groups. A 2-tailed p value <0.05 was considered significant. The chi-square test was performed to calculate the incremental value of LA reservoir and LV untwisting rate over EROA, ESD, and SPAP. Bland–Altman analysis was performed to assess intraobserver and interobserver variability of LV untwisting rate and LA reservoir measurements.
Results
Demographic and clinical characteristics of the overall population at the time of enrollment are described in detail in Table 1 . Assessment of the anatomy of the mitral valve revealed an involvement of the A2 scallop in 11 patients (16%), P2 scallop in 20 (30%), A2-P2 scallops in 9 (13%), commissural scallops in 8 (12%), and a flail leaflet in 19 (29%). As assessed by EROA and VC cut-off values, 20 patients (30%) had mild MR, 24 (36%) had moderate MR, and 23 (34%) had severe MR. With regard to standard echocardiographic evaluation, systolic function, assessed by calculating EF and ESD, was preserved in all patients and all had an SPAP <50 mm Hg at rest ( Table 2 ). Two-dimensional strain analysis showed that in the overall patients population, the mean values of LV strains were preserved and rotational indexes supernormal; in contrast, LA strain (reservoir) and LV untwisting rate, the latter an index of recoil forces, were lower compared to published reference values and data from the healthy subjects of our previous study ( Table 3 ). Moreover, as previously shown, when patients were split into 3 groups according to MR degree, we found that although longitudinal and radial strain were similar regardless of MR degree, circumferential strain and rotational profiles increased in patients with moderate MR and reduced in those with severe MR. Furthermore, LA strain decreased progressively with increasing severity of MR ( Table 3 ). Pearson linear correlations showed that LA reservoir and LV untwisting rate were reciprocally correlated with each other; in addition, they correlate with LA volume, LV sphericity index, SPAP, E / E ′, EROA, and VC ( Table 4 ).
| Characteristics | Patients |
|---|---|
| Men | 37 (55%) |
| Age (years) | 57 ± 18 |
| Body Surface Area (m 2 ) | 1.79 ± 0.22 |
| Heart Rate (b/m’) | 72.5 ± 13.9 |
| Hypertension | 21 (31%) |
| Diabetes Mellitus | 4 (6%) |
| Dyslipidemia ∗ | 12 (18%) |
| Smoker | 5 (7%) |
| Obesity † | 9 (13%) |
| Diuretics | 11 (16%) |
| Beta-blockers | 14 (21%) |
| Calcium Antagonists | 1 (1%) |
| Ace-inhibitors | 9 (13%) |
| Angiotensin II Receptors Antagonist | 9 (13%) |
| Antiarrhythmic | 4 (6%) |
∗ Total cholesterol >5.0 mmol/L (190 mg/dl), low-density lipoprotein cholesterol >3.0 mmol/L (115 mg/dl), or high-density lipoprotein cholesterol <1.2 mmol/L (46 mg/dl) in men and <1.0 mmol/L (40 mg/dl) in women or serum triglycerides >1.7 mmol/L (150 mg/dl).
| Echocardiographic Variables | |
|---|---|
| Morphological and functional left ventricle analysis | |
| End-Diastolic Diameter (mm/m 2 ) | 29.6 ± 3.6 |
| End-Systolic Diameter (mm/m 2 ) | 18.6 ± 4.4 |
| Mass (g/m 2 ) | 94 ± 24 |
| Relative Wall Thickness | 0.33 ± 0.08 |
| End-Diastolic Volume (ml/m 2 ) | 59.5 ± 18 |
| End-Systolic Volume (ml/m 2 ) | 25.2 ± 9.1 |
| Ejection Fraction (%) | 64.2 ± 5.1 |
| Sphericity Index | 0.62 ± 0.07 |
| E/A | 1.32 ± 0.61 |
| Deceleration Time (msec) | 171.4 ± 42.1 |
| E/E′ | 13.7 ± 6.5 |
| Systolic Pulmonary Arterial Pressure (mm Hg) | 35.7 ± 4.6 |
| Morphological and functional mitral valve analysis | |
| One Leaflet Prolapse | 31 (46%) |
| Multileaflet Prolapse | 17 (25%) |
| Flail | 19 (28%) |
| ∗ Mitral Regurgitation | 67 (100%) |
| Mild | 20 (30%) |
| Moderate | 24 (36%) |
| Severe | 23 (34%) |
| Morphological and functional left atrium analysis | |
| Area (cm 2 /m 2 ) | 12.4 ± 3.5 |
| Volume (ml/m 2 ) | 42.9 ± 17 |
∗ Mild: EROA <0.20 cm 2 , VC <0.3 cm; moderate: EROA = 0.20 to 0.39 cm 2 , VC = 0.3 to 0.69 cm; severe: EROA ≥0.40 cm 2 , VC ≥0.7 cm .
| Characteristics | Overall (n = 67) | Degree of Mitral Regurgitation | ||
|---|---|---|---|---|
| Mild (n = 20) | Moderate (n = 24) | Severe (n = 23) | ||
| Global LS (%) | -21.8 ± 1.9 | -21.7 ± 1.8 | -21.9 ± 2.1 | -21.6 ± 1.8 |
| Global CS (%) | -22 ± 4.2 | -20.6 ± 4.7* | -23.4 ± 4.2 | -21.8 ± 3.3* |
| Global radial strain (%) | 43.2 ± 13 | 43 ± 14 | 44 ± 12 | 42.8 ± 13 |
| Basal rotation (degrees) | -7.7 ± 3.1 | -6.5 ± 2.5 | -8.9 ± 3.6 # | -7.7 ± 3.1 |
| Apical rotation (degrees) | 10.7 ± 5.4 | 9.3 ± 4 | 12 ± 5 | 10.5 ± 6 |
| Twist (degrees) | 18.2 ± 6 | 15.5 ± 4.5 | 20.4 ± 5.4 ¶ | 17.6 ± 7 |
| Torsion (°/cm) | 2.4 ± 0.8 | 2 ± 0.6 | 2.7 ± 0.8 # | 2.3 ± 0.9 |
| Untwisting (degrees/s) | -88 ± 35 | -107 ± 18 | -95 ± 31 | -56 ± 33* |
| LA LS (%) | 30.7 ± 9.6 | 38 ± 5.6 | 29.6 ± 9.8 § | 24.8 ± 8* |
| LA Volume | E/E′ | Sphericity Index | SPAP | VC | EROA | LV Recoil | LA LS | |
|---|---|---|---|---|---|---|---|---|
| LA LS | r = -0.44 p = 0.001 | r = -0.58 p <0.001 | r = -0.46 p <0.001 | r = -0.58 p <0.001 | r = -0.52 p <0.001 | r = -0.47 p <0.001 | r = -0.34 p = 0.005 | – – |
| LV Recoil | r = 0.29 p = 0.02 | r = 0.30 p = 0.04 | r = 0.34 p = 0.005 | r = 0.33 p = 0.007 | r = 0.59 p <0.001 | r = 0.51 p <0.001 | – – | r = 0.34 p = 0.005 |
Bland–Altman analysis showed a good agreement of LV untwisting rate and LA reservoir measurements performed by a single observer or 2 different observers ( Figure 1 ).
The duration of follow-up was 24.8 ± 17 months, ranging from 10 days to 75.6 months. Follow-up information was available for all (100%) of the 67 patients. During follow-up, the predefined end points were reached in 33 patients (49%): 5 deaths (3 noncardiac deaths), 9 patients who developed symptoms of heart failure (dyspnea requiring hospitalization), and 19 patients who underwent surgical valve repair/replacement. No patient with mild MR developed events during follow-up, whereas 65% of patients in the moderate MR group and 85% of patients in the severe MR group had a poor outcome. All valve surgical interventions were performed in institutions other than our hospital. Information about surgical indication was available for 13 of 19 patients and included, in most cases (10 of 13, 76%), the occurrence of symptoms and/or LV dilation; only 3 of 13 patients (24%) were recommended for valve surgery because of new-onset atrial fibrillation. A clear description of reasons underlying the surgical decision was missed in 6 patients.
By analyzing baseline echocardiographic examinations of patients developing events (group 1), we found they had larger ESD, increased LV mass with a higher sphericity index, and higher LA volume compared to patients without events. The same applied to parameters such as EROA, VC, E / A , E / E ′, and SPAP. In contrast, patients with events showed lower LV untwisting rate and lower LA reservoir ( Figure 2 , Table 5 ). Main predictors of outcome were EROA, VC, LV ESD, SPAP, LA indexed volume, E / E ′, LA reservoir, and LV untwisting rate ( Table 6 ). However, on multivariate analysis, LA reservoir and LV untwisting rate appeared as the only independent parameters associated with the end point of the study ( Table 6 ).
| Characteristics | Events | p | |
|---|---|---|---|
| Present (n = 33) | Absent (n = 34) | ||
| End-Systolic Diameter (mm/m 2 ) | 35.7 ± 4.6 | 29.5 ± 3.7 | <0.001 |
| LV Mass (g/m 2 ) | 103 ± 20 | 85 ± 23 | 0.002 |
| Sphericity Index | 0.65 ± 0.06 | 0.60 ± 0.07 | 0.007 |
| E/A Ratio | 1.6 ± 0.6 | 1.1 ± 0.5 | 0.001 |
| E/E’ Ratio | 17.9 ± 7.5 | 11.2 ± 4.1 | 0.002 |
| Systolic Pulmonary Arterial Pressure (mm Hg) | 39 ± 5 | 30.4 ± 9 | 0.001 |
| Global Circumferential Strain (%) | -23.4 ± 4.3 | -21 ± 3.8 | 0.024 |
| Untwisting Rate (Recoil) (°/sec) | -67.4 ± 33 | -107.2 ± 25.1 | <0.001 |
| Flail | 11 | 8 | 0.09 |
| Effective Regurgitant Orifice Area (cm 2 ) | 0.41 ± 0.17 | 0.24 ± 0.16 | <0.001 |
| Vena Contracta (mm) | 6.57 ± 2.05 | 4.21 ± 1.62 | <0.001 |
| LA Volume (ml/m 2 ) | 47.5 ± 16.9 | 38.4 ± 16 | 0.04 |
| Longitudinal Strain (Reservoir) (%) | 25 ± 8.4 | 36.4 ± 7.1 | <0.001 |
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