We studied whether evaluation of overall left ventricular (LV) and left atrial (LA) mechanics would be useful to detect subclinical dysfunction in patients with mitral valve prolapse (MVP), mitral regurgitation (MR), and normal LV ejection fraction (EF). Fifty consecutive patients (27 men, mean age 61 ± 19 years) with MVP, MR, and normal systolic function (LVEF ≥60%) were prospectively enrolled and compared with 40 age- and gender-matched healthy subjects (22 men, mean age: 59 ± 16 years). At baseline, 2-dimensional and color-flow Doppler transthoracic echocardiography were performed for MR quantification and analysis of left-chambers mechanics. Patients were divided into groups by severity of MR: mild (n = 14), moderate (n = 19), and severe (n = 17). Left ventricular dimensions, volume and mass, and LA area and volume indices were significantly increased in patients with moderate and severe MR compared with control subjects. Circumferential strain, basal/apical rotations, and twist were significantly enhanced in patients with moderate MR compared with controls; with the exception of basal rotation, they decreased in those with severe MR. Furthermore, LA strain and untwisting rate were progressively and significantly reduced from normal subjects to patients with severe MR. Effective regurgitant orifice area and MR vena contracta were significantly related to most systolic and diastolic function parameters and LA volume as well as LA strain and LV untwisting rate in all patients. In conclusion, cardiac mechanics indices, particularly LA deformation and LV rotational parameters, could help unmask incipient myocardial dysfunction in patients with MVP, especially in those with severe MR and yet normal LVEF.
Mitral valve prolapse (MVP) is the most common cause of organic mitral regurgitation (MR), which generates a chronic volumetric overload silently leading to irreversible left ventricular (LV) dysfunction. Although still advised in current guidelines as a pivotal parameter for evaluation of asymptomatic patients with MR, LV ejection fraction (EF) is a suboptimal marker of systolic function. Furthermore, cardiac remodeling in primary MR also affects the left atrium (LA) beyond the ventricle and is accompanied by mechanical stress-induced hypertrophy and interstitial fibrosis, which increase vulnerability for atrial fibrillation. Relatively new noninvasive parameters, such as strain and rotation obtained by 2-dimensional speckle tracking echocardiography, hold promise to be more reliable indexes of “myocardial performance.” In the present study, we sought to evaluate overall LV and LA mechanics in patients affected by MVP with varying degrees of MR to establish whether LV and LA deformational profiles are effective markers of cardiac function and determine in which patients these parameters could be particularly useful to unmask subclinical cardiac dysfunction.
Methods
Fifty consecutive asymptomatic patients functioning at New York Heart Association Class I and affected by MVP and MR but with normal systolic function (LVEF ≥60%; 27 men, mean age: 61 ± 19 years) were prospectively enrolled. Patients were excluded for the following conditions: presence of other, greater than mild heart valve disease; elevated systolic pulmonary arterial pressure (SPAP) at rest (>50 mm Hg, according to current guidelines) ; heart failure; and/or atrial fibrillation. Furthermore, patients with ischemic heart disease were excluded after treadmill testing in all patients and control subjects. The control group comprised age- and gender-matched healthy subjects (n = 40; 22 men, mean age: 59 ± 16 years). Medical history was obtained for all participants, and each subject underwent physical examination, including body surface area (BSA) measurement 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-chambers mechanics. MVP was diagnosed when the coaptation line appeared 2 mm behind the annular plane using a parasternal long-axis view.
Severity of MR was assessed by effective regurgitant orifice area (EROA), calculated by using the proximal isovelocity surface area method; a cutoff of 0.40 cm 2 EROA was considered suggestive of severe MR. Accordingly, MR was diagnosed as mild when EROA was ≥0.10 and ≤0.19 cm 2 , moderate when EROA was ≥0.20 and ≤0.39 cm 2 ; and severe when EROA was ≥0.40 cm 2 . Quantification of MR was completed by vena contracta measurement, taking into consideration a cutoff value of 0.7 cm for severe MR. Patients were divided into groups by severity of MR: mild (n = 14), moderate (n = 19), and severe (n = 17).
The anatomy of mitral valve apparatus was systematically evaluated to identify prolapsing scallops and/or presence of a flail leaflet; transesophageal echocardiography was performed when appropriate. The LV end-diastolic and end-systolic (ESD) diameters and volumes were measured and indexed to BSA, and EF was calculated using biplane Simpson’s method. To assess LV geometry, end-diastolic relative wall thickness, LV mass/BSA (g/m 2 ), and sphericity index were obtained. 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. Systolic pulmonary artery pressure was calculated through tricuspid regurgitation, and right atrial pressure was added when appropriate.
To properly identify subclinical LV volume overload, both apical (4-, 2-, and 3-chamber) and parasternal short-axis (basal, middle and apical) views were obtained. For atrial longitudinal strain (LS), selected apical 4- and 2-chamber views were acquired. Three consecutive end-expiratory cycles, in gray scale (frame rate = 60 to 80 frames/s), were stored for each view. Analysis of 2-dimensional strain was performed offline using semiautomatic tracking on cardiac images previously transferred to an EchoPac workstation (V.8.0.0, GE). For LA strain analysis, the trigger was positioned at the onset of the P wave on electrocardiogram trace to obtain a negative peak value during LA contraction. Only LS during the reservoir phase was calculated by averaging the positive peak values obtained in 4- and 2-chamber views during LV end-systole. Booster pump function was not included in evaluation of the LA mechanical profile because it is less reproducible and not yet validated. For LV strain analysis, global LS was obtained by automated function imaging, whereas global circumferential (CS) and radial strains were calculated by estimating the average strain derived by myocardial tracking from each view. Ventricular twist (degrees), torsion (degrees), and untwisting rate (degrees/s) were assessed. Finally, to define more precisely in which patients the complex measurements of deformation/rotation could be clinically relevant, we performed an additional analysis of all speckle tracking echocardiography parameters from the pooled patients with moderate and severe MR by dividing them according to a LVESD ≥35 mm and a SPAP ≥35 mm Hg.
Data were analyzed using SPSS (V.17 for Windows, SPSS Inc., Chicago, Illinois). Comparison of continuous variables was performed by 1-way analysis of variance and post hoc Bonferroni testing. Each variable was analyzed for normal distribution using Kolmogorov-Smirnov test. Independent t test was used to compare normally distributed, continuous speckle tracking echocardiography variables between control subjects and all patients. Pearson’s and Spearman’s coefficients were used to test correlation between continuous variables as appropriate. Inter- and intraobserver reproducibility regarding measurement of EROA and LV mechanics parameters were evaluated using an intraclass correlation coefficient; readers were blind to the results. Twenty subjects were randomly selected for this analysis. For any parameter, a p value of ≤0.05 was deemed statistically significant.
Results
Basic clinical and demographic characteristics in the control and MR groups are summarized in Table 1 . Groups were similar in age, gender, BSA, heart rate, blood pressure, and prevalence of cardiovascular risk factors. For basic echocardiographic variables, LV and LA characteristics were increased in patients compared with controls ( Table 2 ). However, this increase was statistically significant only in patients with moderate and severe MR ( Table 2 ). Moreover, there was a significant trend of progressive LV and LA remodeling according to the degree of MR ( Table 2 ). With regard to LV diastolic function, LA dimensions were progressively larger in patients with mild to those with severe MR; the E/A and E/E′ ratios were increased in direct correlation to MR severity ( Table 2 ). Systolic pulmonary artery pressure was higher in patients with moderate and severe MR than in those with mild MR ( Table 2 ). Mitral valve morphology in all patients is detailed in Table 3 . With respect to MR quantification, EROA and vena contracta increased significantly from mild to higher degree of MR ( Table 2 ), and they were respectively correlated with the following LV function parameters: end-diastolic diameter (r = 0.36, p = 0.02; r = 0.44, p = 0.001), ESD (r = 0.33, p = 0.02; r = 0.38, p = 0.008), end-diastolic volume/BSA (rho = 0.62, p = 0.001; rho = 0.55, p = 0.001), end-systolic volume/BSA (rho = 0.67, p <0.001; rho = 0.39, p = 0.009), EF (r = 0.34, p = 0.03; r = 0.47, p = 0.001), E/A ratio (r = 0.72, p = 0.001; r = 0.41, p = 0.02), E/E′ ratio (r = 0.52, p = 0.002; r = 0.42, p = 0.02), and LA volume (r = 0.58, p <0.001; r = 0.43, p = 0.03).
| Characteristics | Severity of MR | |||
|---|---|---|---|---|
| Control (n = 40) | Mild (n = 14) | Moderate (n = 19) | Severe (n = 17) | |
| Age (yrs) | 59 ± 16 | 59 ± 24 | 60 ± 15 | 64 ± 19 |
| Men | 22 (55.0%) | 5 (35.7%) | 9 (47.4%) | 13 (76.4%) |
| BSA (m 2 ) | 1.78 ± 0.18 | 1.79 ± 0.3 | 1.80 ± 0.2 | 1.75 ± 0.2 |
| Heart rate (beats/min) | 74.4 ± 12.8 | 75.0 ± 10.0 | 69.8 ± 15.6 | 68.5 ± 16.0 |
| Systolic arterial pressure (mm Hg) | 130 ± 20 | 128 ± 18 | 132 ± 19 | 135 ± 18 |
| Diastolic arterial pressure (mm Hg) | 85 ± 10 | 84 ± 15 | 88 ± 10 | 88 ± 12 |
| NYHA Class I | 40 (100%) | 14 (100%) | 19 (100%) | 17 (100%) |
| Hypertension | 10 (25%) | 3 (21%) | 4 (21%) | 4 (23.5%) |
| Diabetes mellitus | 4 (10%) | 1 (7%) | 2 (10.5%) | 2 (12%) |
| Smoker | 6 (15%) | 2 (14%) | 2 (10.5%) | 2 (12%) |
| Dyslipidemia ∗ | 11 (27.5%) | 3 (21%) | 4 (21%) | 5 (29%) |
| Angiotensin-converting enzyme inhibitors | 6 (15%) | 1 (7%) | 3 (16%) | 2 (12%) |
| Angiotensin II receptor antagonists | 6 (15%) | 2 (14%) | 2 (10.5%) | 2 (12%) |
| Beta blockers | 13 (32.5%) | 4 (28.5%) | 6 (31.5%) | 5 (29%) |
| Diuretics | 7 (22%) | 2 (14%) | 4 (21%) | 4 (23.5%) |
| Calcium antagonists | 2 (5%) | 1 (7%) | 1 (5%) | 1 (6%) |
| Aspirin | 3 (7.5%) | 1 (7%) | 1 (5%) | 2 (12%) |
∗ Total cholesterol >5.0 mmol/L (190 mg/dl) or 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) according to Mancia G et al, 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28:1462–1536.
| Characteristics | Severity of MR | |||
|---|---|---|---|---|
| Control (n = 40) | Mild (n = 14) | Moderate (n = 19) | Severe (n = 17) | |
| End-diastolic volume (mL/m 2 ) | 40.8 ± 12.9 | 50.4 ± 10.0 | 53.5 ± 15.7 | 71.0 ± 20.0 ∗,† |
| End-systolic volume, (mL/m 2 ) | 39.6 ± 12.1 | 22.2 ± 4.8 | 22.6 ± 7.6 | 31.0 ± 10.0 †,‡ |
| Sphericity index | 0.57 ± 0.06 | 0.60 ± 0.08 | 0.63 ± 0.09 | 0.70 ± 0.10 † |
| End-diastolic diameter (mm) | 46.0 ± 3.6 | 48.8 ± 4.0 | 51.7 ± 6.6 § | 58.0 ± 11.0 ∗,# |
| End-systolic diameter (mm) | 25.0 ± 7.8 | 29.2 ± 4.5 | 29.7 ± 6.3 | 35.0 ± 8.0 ∗,† |
| Relative wall thickness | 0.33 ± 0.04 | 0.36 ± 0.05 | 0.36 ± 0.08 | 0.34 ± 0.08 |
| LV mass (g/m 2 ) | 78.6 ± 20.0 | 74.0 ± 20.0 | 105.7 ± 21.3 §,¶ | 107.0 ± 28.0 ∗,‡ |
| Ejection fraction (%) | 63.0 ± 2.7 | 64.1 ± 3.2 | 64.9 ± 2.9 | 65.3 ± 3.6 |
| LA area (cm 2 /m 2 ) | 8.3 ± 1.3 | 10.2 ± 1.4 | 13.3 ± 3.7 ¶ | 14.5 ± 3.6 ∗,∗∗ |
| LA volume (mL/m 2 ) | 22.6 ± 6.5 | 32.0 ± 10.0 | 46.0 ± 17.7 | 48.6 ± 17.0 ∗,∗∗ |
| E (m/s) | 0.78 ± 0.20 | 0.67 ± 0.14 | 0.99 ± 0.20 ¶ | 1.18 ± 0.40 # |
| E/A | 0.89 ± 0.11 | 0.95 ± 0.12 | 1.09 ± 0.15 § | 1.27 ± 0.21 ∗,‡ |
| Mitral deceleration time (ms) | 174 ± 37 | 176 ± 47 | 173 ± 49 | 170 ± 50 |
| E′ (cm/s) | 10 ± 3 | 7 ± 3 | 6 ± 2 ∗∗ | 6 ± 2 ∗∗ |
| E/E′ | 8.9 ± 3.4 | 10.5 ± 3.9 | 15.4 ± 7.5 | 17.0 ± 6.8 ∗∗ |
| EROA (cm 2 ) | — | 0.14 ± 0.05 | 0.29 ± 0.05 | 0.66 ± 0.28 ††,‡‡ |
| Vena contracta (mm) | — | 3.9 ± 1.2 | 5.4 ± 1 ¶ | 8.5 ± 2.4 ††,‡‡ |
| SPAP (mm Hg) | 26.3 ± 12.0 | 28.5 ± 7.8 | 40.8 ± 16.0 | 41.4 ± 16.0 ‖ |
| Mitral Valve Characteristics | Severity of MR | ||
|---|---|---|---|
| Mild (n = 14) | Moderate (n = 19) | Severe (n = 17) | |
| Flail (P2), n (%) | 0 (0%) | 5 (26.5%) | 10 (58.8%) |
| Prolapse, n (%) | 14 (100%) | 14 (73.5%) | 7 (41.2%) |
| A2 | 4 (28.5%) | 2 (14.2%) | — |
| P2 | 6 (43%) | 3 (21.4%) | 5 (29.5%) |
| A2–P2 | 4 (28.5%) | 4 (28.5%) | — |
| P1–P2 | — | 2 (14.3%) | — |
| P2–P3 | — | 1 (7.2%) | — |
| P1–P2–P3 | — | 1 (7.2%) | 2 (11.7%) |
| P2–P3–A2 | — | 1 (7.2%) | — |
The results of LV and LA mechanics analysis comparing all patients to control subjects showed no difference in LS or radial strain with increased CS, rotations, twist, and torsion in patients; in contrast, LA strain and untwisting rate were significantly lower in patients than in healthy subjects ( Table 4 ). Substantial differences emerged when patients were split into mild, moderate, and severe MR groups ( Table 4 ). In fact, CS significantly increased only in patients with moderate MR compared with control subjects, whereas it showed a trend to decrease in those with severe MR. Moreover, whereas basal rotation progressively increased in proportion to MR severity, apical rotation and twist reached maximum peak in patients with moderate MR, thus decreasing in those with severe MR similarly to CS. Left ventricular twist and torsion also increased according to MR severity, with the highest value in moderate MR patients, thus remaining constant in those with severe MR. However, as MR severity increased, LV untwisting rate decreased ( Figure 1 ). Therefore, patients with severe MR showed the lowest untwisting values compared with controls and other groups of patients ( Table 4 ). Furthermore, LV untwisting showed significant correlations with EROA (r = −0.32, p = 0.033), vena contracta (r = −0.30, p = 0.04), mitral deceleration time (r = 0.69, p <0.001), and most LV function indices: EF (r = 0.45, p = 0.002), sphericity index (r = −0.40, p = 0.007), relative wall thickness (r = −0.60; p <0.001), LS: (r = 0.55, p <0.001), CS: (r = 0.52, p <0.001), twist (r = 0.40, p = 0.007), and LA strain (r = 0.49, p = 0.001).
| Characteristics | Severity of MR | ||||
|---|---|---|---|---|---|
| Controls (n = 40) | Patients (n = 50) | Mild (n = 14) | Moderate (n = 19) | Severe (n = 17) | |
| Global LS (%) | −20.1 ± 2.6 | −20.3 ± 2.5 | −21.4 ± 1.3 | −19.9 ± 3.4 | −19.7 ± 5 |
| Global CS (%) | −19.4 ± 3.3 | −23.0 ± 5 ‡ | −22 ± 4.0 | −24 ± 4.4 ¶ | −21.3 ± 7 |
| Global radial strain (%) | 47.6 ± 12 | 41.4 ± 16 | 42.3 ± 15 | 42.5 ± 20 | 40.5 ± 16 |
| Basal rotation (degrees) | −5.3 ± 2.2 | −8 ± 3 † | −6.5 ± 2.1 | −8.4 ± 3.4 ¶ | −8.8 ± 3.7 ‖ |
| Apical rotation (degrees) | 7.5 ± 5 | 11.6 ± 5.6 ∗ | 9.7 ± 3.8 | 13.4 ± 6.4 ¶ | 11 ± 5.6 |
| Twist (degrees) | 12.6 ± 5.3 | 19.2 ± 6.1 ∗ | 16.3 ± 4.3 | 20.5 ± 7.0 ¶ | 20 ± 6.4 # |
| Torsion (degrees/cm) | 1.9 ± 0.7 | 2.5 ± 0.8 ∗ | 2.2 ± 0.7 | 2.9 ± 1.0 ¶ | 2.6 ± 0.8 # |
| Untwisting (degrees/s) | −104 ± 21 | −79 ± 23 ∗ | −100 ± 11 | −91.2 ± 11 | −70 ± 29 ‖,§ |
| LA LS (%) | 49.9 ± 14 | 38 ± 9.1 ∗ | 44.6 ± 4 | 29 ± 11 | 27 ± 10 # |
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