Functional mitral regurgitation (FMR) is associated with a poor outcome in patients with reduced left ventricular ejection fraction (LVEF). Two recent studies of percutaneous mitral valvular repair therapy reported disparate results, likely due in part to variable risk among FMR patients. The aim of this study is to define echocardiographic factors of prognostic significance in FMR patients, and particularly to compare ischemic and nonischemic FMR. We followed three hundred sixteen consecutive patients (age 60 ± 14 years, men 70%) with FMR and LVEF ≤ 35% between January 2010 and December 2015 (mean follow-up 3.7 years). Patients were categorized into ischemic (39.6%) and nonischemic (60.4%). MR was graded according to the American Society of Echocardiography guidelines. Although echo findings were similar between ischemic and nonischemic patient, the incidence of death, heart transplantation (HT), or LVAD implantation was higher in ischemic than in nonischemic patients (Log rank p = 0.001). In age and gender adjusted multivariate (11 variables) Cox regression analysis, left atrium volume index (LAVI) was associated with death, HT, or LVAD with hazard ratio of 2.1 for patients with FMR (p = 0.003). LAVI greater than 48.7 mL/m 2 predicts adverse outcome in both nonischemic and ischemic FMR (AUC 0.62, p < 0.001). Combined ischemic FMR with LAVI ≥ 48.7 mL/m 2 had the highest incident rate of all groups. In conclusion, despite similar LV function and MR severity, ischemic FMR patients had higher mortality than nonischemic patients. Of all echocardiographic parameters, an LAVI ≥ 48.7 mL/m 2 predicted adverse clinical outcome.
Moderate and severe levels of functional mitral regurgitation (FMR) increase all-cause mortality and heart failure hospitalization in dilated cardiomyopathy patients. Recently two trials evaluated the efficacy of transcatheter mitral valve repair (MitraClip) for patients with FMR and reported disparate clinical results. , Differential risk for events provides a potential explanation for these divergent findings. Echocardiography can quantify FMR, with a value of effective regurgitant orifice area (EROA) ≥ 0.2 cm 2 or regurgitant volume (Rvol) > 30 mL predicting increased mortality and hospitalization. However, sparse data exist for other echo parameters that might predict an adverse outcome. Furthermore, available data are scant comparing the prognostic significance of ischemic versus nonischemic etiology in FMR patients, and none have evaluated the effect of etiology independent of echo variables. Therefore, we analyzed the echoes and clinical characteristics, particularly etiology, that predict the five year outcome in patients with FMR.
Methods
We retrospectively analyzed 316 consecutive patients who had moderate or severe mitral regurgitation (MR) and reduced LVEF ≤ 35% from January 2010 to December 2015 ( Figure 1 ). We excluded cases of MR due to mitral valve prolapse or degenerative mitral valve disease. Patients underwent a clinically indicated comprehensive echocardiogram. For patients with multiple echocardiograms during the study period, we selected the first echo that showed LVEF ≤ 35% and moderate or severe MR. Echocardiograms were performed and analyzed, and mitral regurgitation graded by multiple parameters according to the guidelines of the American Society of Echocardiography. Clinical outcomes were determined by a review of medical records, telephone calls, or review of San Diego County Health Records. We divided FMR patients into two groups, with or without ischemic heart disease, and compared echocardiographic parameters, clinical factors, and outcome. The study was approved by the ethics committee of the University of California at San Diego and waiver of informed consent was granted for this retrospective study.
Echocardiography was performed in the standard manner using commercial ultrasound machines. Left vantrivular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), E/A ratio, E/e’, left atrial volume index (LAVI), and tricuspid regurgitation peak gradient (TRPG) were measured according to standards recommended by the ASE guidelines. , All echo data were stored in workstation (Syngo, Siemens Medical USA, Malvern, PA). We performed offline analysis for measurement of regurgitant volume (Rvol), effective regurgitant orifice area (EROA), and regurgitant fraction (RF), total stroke volume (T-SV) and left ventricular outflow tract stroke volume (LVOT-SV). We used volumetric methods (VOL) to assess Rvol, EROA, and RF. Total stroke volume (T-SV) and left ventricular out flow tract stroke volume (LVOT-SV) were calculated as follows: T-SV = LVEF × LVEDV, and LVOT-SV = LVOT area × LVOT flow velocity time integral, respectively. Rvol, EROA, and RF were calculated using the following formulas: Rvol = T-SV – LVOT-SV (mL), EROA = Rvol/ MR velocity time integral (cm 2 ), and RF = Rvol/Total stroke volume*100 (%), respectively. MR jet reaching the LA posterior wall, width of MR jet, number of MR jets, and pulmonary venous flow reversal of MR were also used to grade severity of MR. LVEF and LA volume were obtained from apical four chamber and two chamber view using the Simpson’s method. We averaged three heart beats for measurements with atrial fibrillation.
Continuous data were presented as mean ± standard deviation (SD) or medians with the interquartile range. We performed Kolmogorov-Smirnov test to evaluate the assumption of normality. We compared factors between nonischemic and ischemic FMR using unpaired t-test for parametric data or Mann-Whitney U-test for nonparametric data. Pearson’s chi-square test was used for categorical variables. Univariate and multivariate Cox hazard regression analyses were performed to find associated factors for death, heart transplantation or left ventricular assist device (LVAD) implantation in patients with FMR. Receiver-operating characteristics (ROC) analysis was performed to identify a cut-off value for worse outcome. The optimal cut-off value was defined by the maximum of Youden’s index (sensitivity+specificity-one). Survival analysis was using Kaplan-Meier method and log-rank test. Values of p < 0.05 were considered to indicate statistical significance. All statistical analyses were performed with the use of the SPSS system (IBM, Chicago, IL).
Results
We retrospectively reviewed three hundred sixteen patients (60 ± 14 years old, men 70.3%) who had LVEF ≤ 35% and were diagnosed with moderate or severe functional mitral regurgitation (FMR). Among them, 125 (39.6%) had FMR due to ischemic etiology (prior infarction or abnormal coronary angiography) while nonischemic etiology was based upon a normal coronary angiogram or radionuclide myocardial scintigraphy. Patient echocardiographic values were shown in Table 1 .
| Factors | Value |
|---|---|
| Age (year) | 60.4 ± 14.1 |
| Men | 222 (70.3%) |
| Non-ischemic functional mitral regurgitation | 191 (60.4%) |
| Ischemic functional mitral regurgitation | 125 (39.6%) |
| Left ventricular ejection fraction (%) | 25.2 ± 7.5 |
| Left ventricular end diastolic volume (ml # ) | 190.8 (151.9 – 260.0) |
| Left ventricular end systolic volume (ml # ) | 137.5 (108.3 – 205.9) |
| E/A ratio # | 2.11 (1.45 – 2.79) |
| E/e’ ratio # | 16.0 (12.2 – 21.3) |
| Left atrial volume index (ml/m 2# ) | 47.1 (38.8 – 55.7) |
| Effective regurgitant orifice area (cm 2# ) | 0.11 (0.06 – 0.19) |
| Regurgitant volume (ml # ) | 16.1 (8.7 – 24.9) |
| Regurgitant fraction (%) | 35.4 ± 17.4 |
| Tricuspid regurgitation peak gradient (mmHg) | 34.7 ± 13.2 |
| Follow-up duration (years) | 3.7 ± 2.4 |
| Echo follow-up duration (years) | 2.7 ± 2.3 |
In our study, the number of patients who met the criteria for severe FMR, (Rvol ≥ 30 mL, EROA ≥ 0.2cm , and RF ≥ 50%) were 56 (17.7%) for Rvol, 69 (21.8%) for EROA, and 79 (25.0%) for RF. Table 2 shows the echocardiographic comparison between patients with nonischemic and ischemic FMR. Ischemic FMR patients were older than nonischemics with a higher prevalence of hypertension, hyperlipidemia, diabetes mellitus, and chronic kidney disease. Atrial fibrillation was similar between the two groups (p = 0.475). Echocardiographic parameters were not significantly different between the two groups ( Table 2 ), nevertheless patients with ischemic FMR had worse survival than those with nonischemic FMR (Log rank p = 0.001) ( Figure 2 ).
| Variable | Non-ischemic FMR (n = 191) | Ischemic FMR (n = 125) | p Valve |
|---|---|---|---|
| Age (years) | 56.5 ± 14.6 | 66.6 ± 10.8 | < 0.001 |
| Men | 124 (64.9%) | 98 (78.4%) | 0.012 |
| Left ventricular ejection fraction (%) | 24.9 ± 7.9 | 25.4 ± 6.7 | 0.575 |
| Left ventricular end diastolic volume (ml # ) | 188.0 (143.0 – 259.5) | 185.0 (145.5 – 247.0) | 0.846 |
| Left ventricular end systolic volume (ml # ) | 137.0 (102.5 – 206.5) | 134.5 (100.0 – 183.5) | 0.731 |
| E/A ratio # | 2.11 (1.44 – 2.62) | 2.28 (1.42 – 3.49) | 0.417 |
| E/e’ ratio # | 16.1 (11.8 – 21.3) | 15.8 (12.4 – 22.2) | 0.082 |
| Left atrial volume index (ml/m 2# ) | 47.7 (38.9 – 57.7) | 44.3 (36.4 – 55.7) | 0.344 |
| Total stroke volume (ml # ) | 45.5 (35.0 – 59.5) | 47.0 (37.5 – 58.5) | 0.355 |
| Left ventricular outflow tract stroke volume (ml # ) | 27.2 (20.9 – 36.0) | 29.9 (23.3 – 37.7) | 0.104 |
| Effective regurgitant orifice area (cm 2# ) | 0.11 (0.07 – 0.19) | 0.10 (0.06 – 0.19) | 0.497 |
| Regurgitant volume (ml # ) | 19.1 (10.8 – 25.8) | 13.6 (7.1 – 23.4) | 0.704 |
| Regurgitant fraction (%) | 37.1 ± 16.9 | 34.8 ± 18.3 | 0.237 |
| Tricuspid regurgitation peak gradient (mmHg) | 32.7 ± 12.0 | 37.5 ± 14.3 | 0.002 |
| Follow-up duration (years) | 3.9 ± 2.4 | 3.3 ± 2.3 | 0.011 |
| Echo follow-up duration (years) | 2.9 ± 2.4 | 2.4 ± 2.1 | 0.030 |
| Coronary artery disease | 6 (3.1%) | 125 (100.0%) | < 0.001 |
| Hypertension | 88 (46.1%) | 90 (72.0%) | < 0.001 |
| Hyperlipidemia | 48 (25.1%) | 83 (66.4%) | < 0.001 |
| Diabetes mellitus | 40 (20.9%) | 57 (45.6%) | <0.001 |
| Cancer | 32 (16.8%) | 16 (12.8%) | 0.423 |
| Chronic kidney disease | 61 (31.9%) | 58 (46.4%) | 0.013 |
| Atrial fibrillation | 20 (10.5%) | 17 (13.6%) | 0.475 |
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