Mitral regurgitation (MR) of even mild severity affects the prognosis of patients with acute coronary syndrome (ACS). The present study retrospectively analyzed 1,142 patients with ACS and MR of varying severity. Of the 95 patients with severe MR, 57 (60%) underwent primary percutaneous coronary intervention only and 38 (40%) underwent coronary artery bypass grafting (CABG) and mitral valve replacement (MVR). The severity of MR was significantly associated with the risk of heart failure but not with in-hospital or long-term mortality. In patients with severe MR, in-hospital mortality was no greater in those treated with CABG and MVR than in those treated with percutaneous coronary intervention alone. However, the incidence of long-term hard events (heart failure and all-cause mortality) was lower in those who had received the combined treatment. Multivariate analysis showed that, compared to percutaneous coronary intervention alone, CABG combined with MVR at the acute phase of ACS resulted in a significantly improved prognosis (odds ratio 0.172, 95% confidence interval 0.046 to 0.649, p = 0.009), even after adjusting for age, left ventricular filling pressure, and ejection fraction. In conclusion, the severity of MR in patients with ACS is associated with long-term heart failure events. Even at the acute phase of ACS, CABG combined with MVR results in an acceptable in-hospital mortality rate. The combined strategy also reduced the long-term hard events.
Mitral regurgitation (MR) complicating acute myocardial infarction portends a grave prognosis. Acute reperfusion does not reduce the mortality to that of patients with less severe MR nor does it reliably restore mitral competence. Despite the advances in modern cardiac care, treating patients with acute myocardial infarction and hemodynamically significant MR remains a clinical challenge. Although revascularization early in the course of acute myocardial infarction, particularly by percutaneous coronary intervention (PCI), can reduce mortality by correcting the occlusion of coronary arteries, the severity of MR still affects the long-term prognosis. This finding has important implications throughout the spectrum of acute coronary syndrome (ACS). Although no randomized trial has been reported, many studies have agreed that MR should not be treated by mitral valve surgery, except in cases of refractory heart failure or cardiogenic shock. The main concern is the high operation-related mortality during the acute phase of acute myocardial infarction. Therefore, the present study of patients with ACS in the acute phase with severe MR investigated whether coronary artery bypass grafting (CABG) combined with mitral valve replacement (MVR) would be a superior strategy compared to PCI alone for reducing the short-term and long-term adverse outcomes.
Methods
The present study retrospectively analyzed 1,233 patients who had received coronary angiography for ACS at Kaohsiung Veterans General Hospital from December 2007 to March 2009. The study protocol was approved by the ethical review board at our institution. From the electrocardiographic findings and biochemical markers of myocardial ischemia and necrosis, the patients were diagnosed with ST-segment elevation myocardial infarction, non–ST-segment elevation myocardial infarction, or unstable angina pectoris. Because 91 patients with aortic valvular disease with more than moderate severity (regurgitation or stenosis) or the lack of complete clinical or follow-up data were excluded, 1,142 patients were selected for the final analysis. Details regarding late outcomes, including heart failure events and all-cause mortality, were obtained by records review, personal interviews, and telephone interviews.
The culprit artery was evaluated in terms of angiographic findings of acute thrombosis or dissected plaque. Single-vessel disease was defined as the absence of other stenosis >70% over nonculprit vascular territories. Multivessel disease was defined as the presence of any other stenosis >70% in the nonculprit vascular territory. Left main disease was classified as double-vessel disease. After catheterization, measurements of the left ventricular filling pressure were performed routinely using a fluid-filled pigtail catheter placed into the left ventricle.
Echocardiography was performed in all patients. The severity of MR was evaluated semiquantitatively from the area of regurgitant jet using color Doppler ultrasonography, and MR was classified as absent or trivial, mild, moderate, or severe, the same system used to classify the outcomes in those with nonischemic mitral valve disease. Left atrial volume measurements were calculated using the biplane area-length method immediately before mitral valve opening. In all patients, the left atrial volumes were indexed to the body surface area. The MR regurgitation volume was calculated as follows: regurgitation volume = (stroke volume of mitral annulus) − (stroke volume of left ventricular outflow tract), where the stroke volumes of the mitral annulus and left ventricular outflow tract were obtained by multiplying the cross-sectional area by the respective time-velocity integral. The MR regurgitation volumes were routinely estimated in patients with MR of moderate or greater severity in our hospital.
Patients with ACS and severe MR were analyzed according to the treatment strategy (PCI alone or CABG and MVR during the index hospitalization). All surgical interventions were performed during the index hospitalization after either diagnostic coronary angiography or coronary intervention. At our hospital, CABG and MVR are preferred instead of mitral valve repair or annuloplasty for patients with ACS and severe MR. No patients in the group received CABG alone or CABG combined with mitral valve repair. After discharge from the index hospitalization, the treatment groups remained unchanged (PCI-alone group or combined CABG and MVR group), regardless of subsequent surgical intervention or PCI.
The only event considered during the index hospitalization was in-hospital death. We also observed the patients’ late course ≥2 years (median of 32 months) after the index hospitalization. All-cause mortality and rehospitalization for congestive heart failure were defined as hard cardiovascular events. Heart failure with rehospitalization was defined as the occurrence of any of ≥1 of the following events: (1) worsening exercise tolerance and respiratory distress with New York Heart Association class III or IV symptoms or (2) the presence of pulmonary rales or chest radiograph showing pulmonary congestion, requiring oral or intravenous diuretics during an in-hospital stay.
The SPSS software (SPSS, Chicago, Illinois) was used for all statistical analyses. All continuous variables are presented as the mean ± SD. The comparison of clinical characteristics was performed using chi-square analysis for categorical variables. Analysis of variance and the post hoc test for unpaired data were used to evaluate the significance of the differences between the groups. A p value of <0.05 was considered statistically significant. The potential predictors of in-hospital mortality and long-term prognosis were tested using univariate and multivariate logistic regression analyses. Variables considered as potential predictors for multivariate modeling were selected from the univariate analysis results and subsequently selected with entry and retention in the model set at a significance level of 0.05. To evaluate the effect of covariates on in-hospital mortality and the incidence of hard cardiovascular events, the relative risk and 95% confidence intervals were calculated as hazard ratios derived from the Cox proportional hazards model.
Results
The baseline characteristics of the study cohort of the 1,142 patients with ACS (444 with unstable angina, 151 with non–ST-segment elevation myocardial infarction, and 547 with ST-segment elevation myocardial infarction) are listed in Table 1 . Of the 95 patients with ACS and severe MR, 38 (40%) were treated with CABG and MVR with or without primary PCI and 57 underwent PCI alone during the index hospitalization. Of the 57 patients treated with PCI alone, 8 died during the index hospitalization. The echocardiographic findings of the 49 survivors during the late course confirmed the existence of severe MR in all, except 3, in whom the MR severity was less than severe (2 moderate, 1 mild). After the index hospitalization, 18 (31.6%) of the 57 treated by PCI alone received either MVR alone or CABG combined with MVR. The severity of MR tended to correlate positively with age, regurgitation volume, pulmonary artery systolic pressure, maximum indexed left atrial volume, left ventricular filling pressure, and a history of coronary artery disease, multivessel disease, renal dysfunction, and systolic dysfunction. Compared to the other groups, the patients with ACS and severe MR were more likely to be women and were much more likely to have a history of unstable angina and non–ST-segment elevation myocardial infarction.
| Characteristic | MR Degree | p Value | |||
|---|---|---|---|---|---|
| 0 (n = 620) | 1+ (n = 309) | 2+ (n = 118) | 3+ (n = 95) | ||
| Age (years) | 65 ± 14 | 67 ± 13 | 69 ± 14 | 70 ± 22 | 0.003 ⁎ † |
| Gender | <0.0001 | ||||
| Male | 536 | 256 | 74 | 53 | |
| Female | 94 | 53 | 44 | 42 | |
| Hypertension | 344 (55.5%) | 206 (66.7%) | 74 (62.7%) | 49 (51.6%) | 0.024 |
| Diabetes mellitus | 174 (28.1%) | 112 (36.2%) | 52 (44.1%) | 37 (38.9%) | 0.001 |
| Previous coronary artery disease | 136 (21.9%) | 71 (23.7%) | 30 (25.4%) | 33 (34.7%) | 0.002 |
| Creatinine (mg/dl) | 1.3 ± 1.1 | 1.6 ± 1.7 | 2.1 ± 2.1 | 2.1 ± 2.6 | <0.0001 ⁎ † ‡ § ∥ |
| Peak creatine kinase (U/L) ¶ | 2,216 ± 2.32 | 2,048 ± 2,342 | 1,909 ± 1,854 | 1,494 ± 1,628 | 0.198 |
| Pulmonary artery systolic pressure (mm Hg) | 29 ± 8 | 35 ± 9 | 42 ± 11 | 46 ± 11 | <0.0001 ⁎ † ‡ § ∥ # |
| Left ventricular ejection fraction | 52 ± 9 | 47 ± 10 | 42 ± 10 | 43 ± 12 | <0.0001 ⁎ ‡ § ∥ |
| Left ventricular filling pressure (mm Hg) | 14.2 ± 5.2 | 17.3 ± 6.5 | 22.7 ± 7.2 | 24.8 ± 7.1 | <0.0001 ⁎ † ‡ § ∥ # |
| Mitral regurgitant volume (ml) | 39 ± 17 | 74 ± 28 | <0.0001 | ||
| Maximum indexed left atrial volume (ml/m 2 ) | 29.6 ± 9.6 | 31.9 ± 12.5 | 42.9 ± 16.1 | 56.4 ± 26.6 | <0.0001 ⁎ † ‡ § ∥ # |
| Respiratory failure | 20 (3.2%) | 39 (12.6%) | 18 (15.3%) | 15 (15.8%) | 0.091 |
| Unstable angina pectoris | 238 (38.4%) | 103 (33.3%) | 41 (34.7%) | 62 (65.3%) | <0.0001 |
| Acute myocardial infarction | 0.021 | ||||
| Anterior wall | 200/382 (52.4%) | 100/206 (48.5%) | 25/77 (32.50%) | 8/33 (24.20%) | |
| Inferior wall | 112/382 (29.3%) | 48/206 (23.3%) | 21/77 (27.30%) | 8/33 (24.20%) | |
| Lateral wall | 12/382 (3.1%) | 11/206 (5.3%) | 2/77 (2.60%) | 0/33 (0%) | |
| Non–ST-segment elevation myocardial infarction | 58/382 (15.2%) | 47/206 (22.8%) | 29/77 (37.70%) | 17/33 (51.5%) | |
| Killip classification ¶ | <0.0001 | ||||
| I | 218/382 (57.1%) | 76/206 (36.9%) | 17/77 (22.10%) | 7/33 (21.20%) | |
| II | 124/382 (32.5%) | 74/206 (35.9%) | 27/77 (35.10%) | 10/33 (30.3%) | |
| III | 32/382 (8.4%) | 44/206 (21.4%) | 30/77 (39.00%) | 13/33 (39.4%) | |
| IV | 8/382 (2.10%) | 12/206 (5.8%) | 3/77 (3.90%) | 3/33 (9.10%) | |
| Diseased coronary arteries (n) | <0.0001 | ||||
| 0 | 26 (4.2%) | 1 (0.3%) | 1 (0.8%) | 0 (0%) | |
| 1 | 356 (57.4%) | 153 (49.5%) | 45 (38.1%) | 16 (16.8%) | |
| 2 | 125 (20.2%) | 80 (25.9%) | 32 (27.1%) | 38 (40.0%) | |
| 3 | 113 (18.2%) | 75 (24.3%) | 40 (33.9%) | 41 (43.2%) | |
| Coronary artery bypass graft surgery during index hospitalization | 70 (11.3%) | 32 (10.4%) | 16 (13.6%) | 38 (40%) ⁎⁎ | <0.0001 |
⁎ ACS without MR versus ACS with severe MR, p <0.05 in post hoc analysis.
† ACS with mild MR versus ACS with severe MR, p <0.05 in post hoc analysis.
‡ ACS without MR versus ACS with mild MR, p <0.05 in post hoc analysis.
§ ACS without MR versus ACS with moderate MR, p <0.05 in post hoc analysis.
∥ ACS with mild MR versus ACS with moderate MR, p <0.05 in post hoc analysis.
¶ Only for patients with acute myocardial infarction.
# ACS with moderate MR versus ACS with severe MR, p <0.05 in post hoc analysis.
⁎⁎ All patients in this group received both CABG and MVR; subjects were considered hypertensive if they had high blood pressure or were receiving antihypertension medication at the index examination.
The univariate analysis of in-hospital mortality showed that the following factors were significantly associated with in-hospital mortality: acute myocardial infarction, high Killip classification, multivessel disease, advanced age, female gender, diabetes, left ventricular systolic dysfunction, elevated left ventricular filling pressure, elevated pulmonary artery systolic pressure, MR severity, maximum indexed left atrial volume, and the presence of respiratory failure. However, only advanced age (hazard ratio 1.008/1-year increase, 95% confidence interval 1.000 to 1.017, p = 0.048) and respiratory failure requiring ventilator support (hazard ratio 8.715, 95% confidence interval 3.454 to 21.422, p <0.0001) were independently associated with mortality during the index hospitalization.
The results of the univariate and multivariate analyses of long-term hard events (including heart failure and all-cause mortality) are listed in Tables 2 to 3 . Multivariate analysis showed that heart failure events were associated with hypertension, left ventricular ejection fraction, and MR severity. Multivariate analysis showed that the only factors significantly associated with all-cause mortality in late course were left ventricular ejection fraction and respiratory failure requiring ventilator support during the index hospitalization.
| Variable | HR | 95% CI | p Value |
|---|---|---|---|
| Univariate | |||
| Acute myocardial infarction | 1.168 | 0.767–1.778 | 0.469 |
| Diseased coronary arteries (per 1-vessel increase) | 1.528 | 1.214–1.924 | <0.0001 |
| Previous coronary artery disease | 1.113 | 0.897–1.896 | 0.264 |
| Respiratory failure | 2.34 | 1.326–4.128 | 0.003 |
| Renal insufficiency | 1.043 | 0.933–1.165 | 0.46 |
| Peak creatinine kinase (per 100-U increase) | 1.008 | 0.997–1.019 | 0.176 |
| Age (per 1-year increase) | 1.009 | 0.999–1.018 | 0.069 |
| Female gender | 0.922 | 0.554–1.536 | 0.756 |
| Diabetes mellitus | 1.5 | 0.992–2.267 | 0.055 |
| Hypertension | 2.326 | 1.482–3.765 | <0.0001 |
| Left ventricular filling pressure (per 1-mm Hg increase) | 1.068 | 1.041–1.096 | <0.0001 |
| Left ventricular ejection fraction (per 1% increase) | 0.948 | 0.929–0.967 | <0.0001 |
| Pulmonary artery systolic pressure (per 1-mm Hg increase) | 1.057 | 1.038–1.075 | <0.0001 |
| Mitral regurgitation severity (per 1 class increase) | 1.658 | 1.379–1.994 | <0.0001 |
| Regurgitation volume (per 10-ml increase) | 0.996 | 0.983–1.009 | 0.556 |
| Maximal indexed left atrial volume (per 1-ml/m 2 increase) | 1.012 | 1.006–1.019 | <0.0001 |
| Multivariate | |||
| Diseased coronary arteries (per 1-vessel increase) | 1.148 | 0.885–1.491 | 0.298 |
| Respiratory failure | 1.103 | 0.526–2.315 | 0.795 |
| Hypertension | 2.179 | 1.334–3.534 | 0.002 |
| Left ventricular filling pressure (per 1-mm Hg increase) | 1.011 | 0.984–1.267 | 0.471 |
| Left ventricular ejection fraction (per 1% increase) | 0.971 | 0.946–0.996 | 0.023 |
| Pulmonary artery systolic pressure (per 1-mm Hg increase) | 1.021 | 0.994–1.048 | 0.127 |
| Mitral regurgitation severity (per 1 class increase) | 1.347 | 1.046–1.734 | 0.021 |
| Maximal indexed left atrial volume (per 1-ml/m 2 increase) | 1.005 | 0.997–1.012 | 0.23 |
| HR | 95% CI | p Value | |
|---|---|---|---|
| Univariate | |||
| Acute myocardial infarction | 1.87 | 1.132–3.088 | 0.014 |
| Diseased coronary arteries (per 1-vessel increase) | 1.665 | 1.290–2.148 | <0.0001 |
| Previous coronary artery disease | 1.321 | 0.904–1.768 | 0.196 |
| Respiratory failure | 8.791 | 5.228–14.617 | <0.0001 |
| Renal insufficiency | 1.139 | 1.035–1.253 | 0.008 |
| Peak creatinine kinase (per 100-U increase) | 0.993 | 0.968–1.074 | 0.132 |
| Age (per 1-year increase) | 1.013 | 0.999–1.028 | 0.071 |
| Female gender | 2.08 | 1.289–3.357 | 0.003 |
| Diabetes mellitus | 2.397 | 1.532–3.750 | <0.0001 |
| Hypertension | 1.933 | 1.178–3.170 | 0.009 |
| Left ventricular filling pressure (per 1-mm Hg increase) | 1.104 | 1.073–1.135 | <0.0001 |
| Left ventricular ejection fraction (per 1% increase) | 0.922 | 0.902–0.944 | <0.0001 |
| Pulmonary artery systolic pressure (per 1-mm Hg increase) | 1.071 | 1.051–1.092 | <0.0001 |
| Mitral regurgitation severity (per 1 class increase) | 1.697 | 1.388–2.074 | <0.0001 |
| Regurgitation volume (per 10-ml increase) | 0.986 | 0.969–1.003 | 0.107 |
| Maximal indexed left atrial volume (per 1-ml/m 2 increase) | 1.012 | 1.005–1.019 | 0.001 |
| Multivariate | |||
| Acute myocardial infarction | 1.126 | 0.646–2.783 | 0.336 |
| Diseased coronary arteries (per 1-vessel increase) | 0.932 | 0.628–1.355 | 0.68 |
| Respiratory failure | 3.146 | 1.399–7.071 | 0.006 |
| Female gender | 1.589 | 0.798–3.163 | 0.187 |
| Diabetes mellitus | 1.246 | 0.634–2.413 | 0.515 |
| Hypertension | 1.71 | 0.849–3.445 | 0.133 |
| Left ventricular filling pressure (per 1-mm Hg increase) | 1.089 | 0.939–1.266 | 0.683 |
| Left ventricular ejection fraction (per 1% increase) | 0.951 | 0.910–0.993 | 0.023 |
| Pulmonary artery systolic pressure (per 1-mm Hg increase) | 0.997 | 0.958–1.038 | 0.883 |
| Mitral regurgitation severity (per 1 class increase) | 1.118 | 0.782–1.599 | 0.542 |
| Maximum indexed left atrial volume (per 1 ml/m 2 increase) | 1.015 | 0.998–1.032 | 0.076 |
The baseline characteristics of the patients with ACS and severe MR stratified by treatment strategy are listed in Table 4 . Patients with renal dysfunction tended to receive surgical intervention during the acute phase of ACS. The in-hospital mortality did not significantly differ between the 2 treatment groups (14% for initial PCI treatment vs 10.5% for immediate CABG and MVR). In the group that received CABG and MVR, 6 heart failure events occurred during the follow-up period, 4 of which were fatal. In terms of hard events in the late course, the group treated with combined CABG and MVR had a better prognosis compared to the group treated with PCI alone (17.6% vs 46.9%). Figure 1 shows the bar graph for the short-term and long-term events stratified by MR severity and treatment strategies. The results of the univariate and multivariate analyses of all hard events that occurred in the late course are listed in Table 5 . The multivariate analysis model showed that patients who had experienced respiratory failure requiring ventilator support during the index hospitalization had an increased incidence of long-term hard events. In the patients with ACS and severe MR, the combined CABG and MVR strategy did reduce the incidence of all hard events in the late course (hazard ratio 0.172, 95% confidence interval 0.046 to 0.649, p = 0.009).
