Patients with secondary mitral regurgitation (SMR) often have extramitral valve cardiac involvement, which can influence the prognosis. SMR can be defined according to groups of extramitral valve cardiac involvement. The prognostic implications of such groups in patients with moderate and severe SMR (significant SMR) are unknown. A total of 325 patients with significant SMR were classified according to the extent of cardiac involvement on echocardiography: left ventricular involvement (group 1), left atrial involvement (group 2), tricuspid valve and pulmonary artery vasculature involvement (group 3), or right ventricular involvement (group 4). The primary end point was all-cause mortality. The prevalence of each cardiac involvement group was 17% in group 1, 12% in group 2, 23% in group 3%, and 48% in group 4. Group 3 and group 4 were independently associated with all-cause mortality (hazard ratio 1.794, 95% confidence interval 1.067 to 3.015, p = 0.027 and hazard ratio 1.857, 95% confidence interval 1.145 to 3.012, p = 0.012, respectively). In conclusion, progressive extramitral valve cardiac involvement (group 3 and group 4) was independently associated with all-cause mortality in patients with significant SMR.
Guideline-directed medical therapy for heart failure (including cardiac resynchronization therapy [CRT]) has been demonstrated to reverse left ventricular (LV) remodeling and reduce secondary mitral regurgitation (SMR) in selected patients. , However, patients who remain with moderate-to-severe or severe SMR despite guideline-directed medical therapy exhibit high morbidity and mortality. The high operative risk and relatively high SMR recurrence rate may explain the low referral rate for mitral valve intervention. More recently, transcatheter mitral valve repair with MitraClip (Abbott, Abbott Park, Illinois) was demonstrated to improve the prognosis of selected patients with heart failure and SMR with symptoms refractory to medical therapy. The echocardiographic criteria that indicate the need for mitral valve intervention comprise measures of SMR severity, LV ejection fraction (LVEF), and LV volumes. However, the spectrum of cardiac abnormalities that accompany SMR and that influence patient outcomes is broader. Cardiac classification algorithms have been applied to severe aortic stenosis and have shown that extra-aortic valve, cardiac involvement provides incremental prognostic value over measures of aortic stenosis severity. Accordingly, the present study proposes an algorithm to divide patients with SMR into groups based on their extramitral valve, cardiac involvement and evaluated its prognostic implications.
Methods
Patients with moderate and severe SMR (significant SMR) and reduced LVEF <50% were identified between 1999 and 2018 from ongoing registries of patients with SMR at the Leiden University Medical Center (The Netherlands) and are included in this analysis. Patients were classified into 4 groups of cardiac involvement, based on the presence of extramitral valvular cardiac involvement derived from the first echocardiogram performed with patients in a hemodynamic stable condition showing significant SMR ( Figure 1 ): group 1: LV involvement (LV end-diastolic diameter ≥57 mm and/or LVEF <50%); group 2: left atrial (LA) involvement (LA volume index >34 ml/m 2 and/or history of atrial fibrillation); group 3: tricuspid valve or pulmonary artery vasculature involvement (systolic pulmonary artery pressure [SPAP] ≥40 mm Hg and/or significant tricuspid regurgitation [TR]); group 4: right ventricular (RV) involvement (tricuspid annular plane systolic excursion [TAPSE] ≤17 mm). Importantly, patients were classified according to the highest cardiac involvement group; thus, for example, if patients had LVEF <50% and TAPSE ≤17 mm, they were included in group 4.
Patients with previous mitral valve intervention (surgical mitral valve repair, mitral valve replacement, or transcatheter edge-to-edge mitral valve repair) or incomplete echocardiographic data to determine the extramitral valvular cardiac involvement were excluded. Clinical and demographic data were collected using the departmental patient information system. For retrospective analysis of clinically acquired data which were anonymously handled, the institutional review board waived the need for patient written informed consent.
Transthoracic echocardiography was performed with the patients at rest, lying in the left lateral decubitus position, using commercially available ultrasound systems (GE Vingmed Ultrasound, General Electric, Milwaukee, Wisconsin) equipped with 3.5 MHz or M5S transducers. Two-dimensional and Doppler data were acquired from parasternal, apical, and subcostal views. LV end-diastolic diameter was measured on the parasternal long-axis view. The apical 2- and 4-chamber views were used to measure the LV end-diastolic and end-systolic volumes, and LVEF was calculated according to Simpson’s biplane method. LA volumes were measured at the end of ventricular systole on the 2- and 4-chamber apical views, using the biplane method of disks, and indexed for body surface area (LA volume index). Stroke volume was calculated with the following equation: Stroke volume = LV outflow tract velocity time integral × cross-sectional area of the LV outflow tract. The severity of mitral regurgitation was assessed according to current recommendations, using qualitative, semiquantitative, and quantitative data. If measurable, quantitative measurements were conducted according to the proximal isovelocity surface area method, for which the effective regurgitant orifice area was measured and regurgitant volume was calculated by multiplying effective regurgitant orifice area by the mitral valve velocity time integral. , The severity of TR was semiquantitatively assessed using vena contracta width: mild <0.3 cm, moderate 0.3 to 0.69 cm, and severe ≥0.7 cm. , Significant TR was defined as moderate or severe TR. RV systolic function was assessed using the TAPSE measured on the focused 4-chamber apical view and M-mode. , To estimate the SPAP the RV pressure was calculated from the peak velocity of the TR jet, according to the simplified Bernoulli’s equation, to which the right atrial pressure was identified by the inspiratory collapse and diameter of the inferior vena cava were added. ,
Patients were followed up for the occurrence of mitral valve intervention (i.e., surgical mitral valve repair, mitral valve replacement, and percutaneous edge-to-edge mitral valve repair) and all-cause mortality. The primary outcome was all-cause mortality. Mortality data were collected from the departmental patient information system, which is linked to the governmental death registry database. In addition, to evaluate the heart failure treatment in this population, the occurrence of CRT was investigated.
Continuous data are presented as mean ± SD when normally distributed or as median and interquartile range when non-normally distributed. Categorical data are presented as frequencies and percentages. Comparison of continuous data, when normally distributed, was performed using the one-way analysis of variance analysis with Bonferroni’s post hoc analysis or, when non-normally distributed, with the Kruskal-Wallis test. Categorical data were compared using the chi-square test. Kaplan-Meier analysis was used to estimate the event-free survival rates of patients in the various groups during follow-up. The event-free survival rates were compared using the log-rank test. Univariable Cox proportional hazards analysis was performed to evaluate the association between the extramitral valvular cardiac involvement groups and other clinical and echocardiographic variables with all-cause mortality. Mitral valve intervention was also included as a time-dependent variable in this analysis. The hazard ratio and 95% confidence interval were reported. In the univariable analysis, clinically relevant variables were selected and included in the multivariable Cox proportional hazards model. A two-sided p <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0. (Armonk, New York: IBM Corp.)
Results
A total of 325 patients (mean age 69 ± 10 years, 66% male) with severely reduced LVEF (mean 29 ± 9%) were included. The distribution of patients across the different groups of cardiac involvement is presented in Figure 2 . The clinical and echocardiographic characteristics of the overall population and for each cardiac involvement group are listed in Tables 1 and 2 , respectively. Patients in group 4 (RV involvement) were older and had worse kidney function compared with group 1 (LV involvement). During a median follow-up of 67 months (interquartile range: 27 to 121 months), 192 patients died (59%), 148 patients (46%) underwent mitral valve intervention and 258 patients (79%) received CRT ( Table 3 ). The Kaplan-Meier analysis for all-cause mortality in the total population is shown in Figure 3 . Patients in group 1 had better survival as compared with the patients in groups 3 and 4. The 1- and 8-year mortality rates for patients in group 1 were 6% and 33% respectively, which is lower than the mortality rates of patients in groups 3 and 4, which were 12% and 17% at 1-year and 53%, and 57% at 8 years of follow-up, respectively.
| Variable | Total population (n=325) | Group 1 LV involvement (n=54) | Group 2 LA involvement (n=40) | Group 3 TV or pulmonary artery vasculature involvement (n=76) | Group 4 RV involvement (n=155) | p-value |
|---|---|---|---|---|---|---|
| Male | 213 (66%) | 32 (59%) | 25 (63%) | 48 (63%) | 108 (70%) | 0.480 |
| Age (years) | 69 ± 10 | 62 ± 12 | 67 ± 12 | 66 ± 10 | 68 ± 9 * | 0.001 |
| Body surface area (m 2 ) | 1.9 ± 0.21 | 1.9 ± 0.21 | 1.9 ± 0.23 | 1.9 ± 0.21 | 1.9 ± 0.20 | 0.987 |
| Creatinine (µmol/L) | 101 (81-136) | 90 (75-117) | 103 (75-132) | 98 (87-133) | 109 (85-153) * | 0.009 |
| NYHA ≥ II | 306 (94%) | 51 (94%) | 38 (95%) | 71 (93%) | 146 (94%) | 0.987 |
| Atrial fibrillation | 172 (53%) | 0 (0%) | 23 (58%) | 40 (53%) | 109 (70%) | <0.001 |
| CRT | 33 (10%) | 3 (6%) | 5 (13%) | 5 (7%) | 20 (13%) | 0.279 |
| Diabetes mellitus | 69 (21%) | 9 (17%) | 7 (18%) | 15 (20%) | 38 (25%) | 0.550 |
| Hypertension | 132 (41%) | 22 (41%) | 18 (45%) | 28 (37%) | 64 (41%) | 0.850 |
| COPD | 38 (12%) | 4 (7%) | 3 (8%) | 10 (13%) | 21 (14%) | 0.509 |
| Beta-blocker | 236 (73%) | 41 (76%) | 28 (70%) | 54 (71%) | 113 (73%) | 0.911 |
| ACE or ARB | 263 (81%) | 46 (85%) | 34 (85%) | 64 (84%) | 119 (77%) | 0.344 |
| Diuretics | 278 (86%) | 42 (78%) | 29 (73%) | 66 (87%) | 141 (91%) | 0.008 |
⁎ p<0.05 versus stage 1. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; LA = left atrial; LV = left ventricular; NYHA = New York Heart Association; RV = right ventricular; TV = tricuspid valve.
| Variable | Total population (n=325) | Group 1 LV involvement (n=54) | Group 2 LA involvement (n=40) | Group 3 TV or pulmonary artery vasculature involvement (n=76) | Group 4 RV involvement (n=155) | p-value |
|---|---|---|---|---|---|---|
| LV end-diastolic diameter (mm) | 67 ± 10 | 67 ± 9 | 70 ± 11 | 67 ± 11 | 65 ± 9 | 0.073 |
| LV end-diastolic volume (ml) | 196 (144-250) | 209 (172-255) | 200 (129-268) | 193 (144-248) | 185 (139-240) | 0.304 |
| LV end-systolic volume (ml) | 142 (97-184) | 155 (110-188) | 135 (88-186) | 138 (97-181) | 136 (93-186) | 0.468 |
| Stroke volume (ml) | 43 ± 13 | 46 ± 12 | 47 ± 12 | 43 ± 11 | 40 ± 14 * , † | 0.005 |
| LV ejection fraction (%) | 29 ± 9 | 28 ± 9 | 30 ± 9 | 30 ± 9 | 28 ± 9 | 0.452 |
| Left atrial volume index (ml/m 2 ) | 38 (29-49) | 25 (19-30) | 40 (34-52) * | 38 (35-49) * | 44 (36-56) * | <0.001 |
| SPAP (mmHg) | 43 ± 13 | 28 ± 7 | 32 ± 6 | 49 ± 12 * , † | 49 ± 12 * , † | <0.001 |
| TAPSE (mm) | 18 (13-20) | 20 (19-22) | 19 (18-21) | 20 (18-23) | 13 (11-15) * , † ‡ | <0.001 |
| EROA (mm2) | 20 (14-29) | 16 (12-20) | 19 (11-24) | 20 (15-30) * | 20 (15-30) * | 0.006 |
| Regurgitant volume (ml) | 31 ± 15 | 28 ± 15 | 31 ± 13 | 33 ± 16 | 31 ± 15 | 0.405 |
| Mitral regurgitation | 0.002 | |||||
| Moderate | 52 (16%) | 15 (28%) | 6 (15%) | 9 (12%) | 22 (14%) | |
| Moderate-severe | 129 (40%) | 28 (52%) | 20 (50%) | 27 (36%) | 54 (35%) | |
| Severe | 144 (44%) | 11 (20%) | 14 (35%) | 40 (53%) | 79 (51%) | |
| Tricuspid regurgitation | <0.001 | |||||
| Moderate | 74 (23%) | 0 (0%) | 0 (0%) | 18 (25%) | 56 (37%) | |
| Severe | 23 (7%) | 0 (0%) | 0 (0%) | 6 (8%) | 17 (11%) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
