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Ann Thorac Surg 2006;81:2128-2134
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Impact of No-to-Moderate Mitral Regurgitation on Late Results After Isolated Coronary Artery Bypass Grafting in Patients With Ischemic Cardiomyopathy

Michele Di Mauro, MD a , Gabriele Di Giammarco, MD a , Giuseppe Vitolla, MD a , Marco Contini, MD b , Angela L. Iacò, MD b , Antonio Bivona, MD b , Luca Weltert, MD b , Antonio M. Calafiore, MD b , *

a Division of Cardiac Surgery, University "G. D'Annunzio," Chieti
b Division of Cardiac Surgery, European Hospital, Rome, Italy

Accepted for publication January 13, 2006.

* Address correspondence to Dr Calafiore, Clinica Cardiochirurgica, European Hospital, Via Portuense 700, 00198 Rome, Italy. (Email: calafiore{at}unich.it).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: This study analyzes retrospectively a cohort of patients with ischemic cardiomyopathy (ejection fraction ≤0.30) who underwent isolated coronary artery bypass grafting to evaluate the impact of no-to-moderate mitral regurgitation (MR) on long-term results.

METHODS: From January 1988 to December 2002, 6,108 patients had isolated coronary artery bypass grafting. Two hundred thirty-nine (3.9%) had ischemic cardiomyopathy; 60 patients had no, 102 had mild, and 77 had moderate MR. Using propensity score, a group of 70 patients with no or mild MR (group A) was case-matched with a group of 70 patients with moderate MR (group B) to obtain two groups with similar preoperative characteristics.

RESULTS: Nine patients (6.4%) died within the first 30 days; all deaths were cardiac-related. There was no difference in the early results between groups. Patients in group B showed lower freedom from death, from cardiac death, from cardiac death and ischemic events, and from death and New York Heart Association class III and IV than patients in group A. Cox analysis confirmed that moderate MR was an independent variable for worse late outcome in this subgroup of patients. Functional and echocardiographic results, after a mean of 62 ± 28 months in 87.8% of survivors, showed a significant impairment of New York Heart Association class (from 2.2 ± 0.5 to 2.8 ± 0.6; p < 0.001) and MR degree (from 2.0 to 2.7 ± 1.0; p = 0.023) in patients with preoperative moderate MR.

CONCLUSIONS: This study confirms that moderate ischemic MR has an important negative impact on survival and quality of life of patients with severely impaired left ventricular function, treated by coronary artery bypass grafting alone.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Ischemic cardiomyopathy can be defined as severe left ventricular (LV) dysfunction caused by either acute myocardial infarction or chronic coronary artery disease [1, 2]. It represents the most common cause of heart failure in the United States [3]. Although cardiac transplantation is still considered the gold standard in the treatment of ischemic cardiomyopathy, a shortage of donors has strongly limited its wide application [4]. Therefore, several studies have investigated the impact of isolated coronary artery bypass grafting (CABG) on early and late outcomes of patients with poor LV function. Most of them stated that CABG can improve prognosis and heart failure symptoms, and restore LV function in those patients who showed viable myocardium [5–10] at one of the common myocardial viability testing procedures [11]. However, myocardial viability seems not to be the only predictor of myocardial recovery after isolated CABG [12].

Ischemic mitral regurgitation (MR) can impair the outcome of patients with previous myocardial infarction [13, 14], especially in case of severe LV dysfunction. Although it is widely accepted that moderate-to-severe and severe MR needs surgical correction, the debate is still focused on the role of this surgery in the treatment of moderate MR [15–24]. Hence, we analyzed retrospectively a cohort of patients with ischemic cardiomyopathy who underwent isolated CABG to evaluate the impact of no, mild, or moderate MR on long-term results.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
From January 1988 to December 2002, 6,108 patients had isolated CABG. Two hundred thirty-nine of them (3.9%) had ischemic cardiomyopathy, defined as ejection fraction of 0.30 or less and presenting with either a history of myocardial infarction or severe coronary artery disease [1, 3]. Use of our database was authorized by our institutional review board on October 13, 2004. The authorization waived patient consent.

Preoperative echocardiogram showed that in 176 patients there was some degree of functional chronic MR. In no case was MR caused by structural mitral disease, but was a direct or indirect consequence of the ischemic heart disease. The presence and entity of MR were evaluated by using colored areas of jet regurgitation and jet to left atrial area ratios [25]. Severity was graded as mild (1 of 4, if regurgitant area was up to 4 cm2), moderate (2 of 4, from 4 to 6 cm2), moderate to severe (3 of 4, from 6 to 8 cm2), and severe (4 of 4, more than 8 cm2). In 165 patients the left atrial area was calculated, and the percentage of regurgitant area was considered 1 of 4 if the regurgitant area was less than 25% of the left atrial area, 2 of 4 if it was from 25% to 40%, 3 of 4 if it was from 40% to 50%, and 4 of 4 if it was higher than 50%.

Sixty patients had no MR whereas 102 showed mild and 77 moderate MR. Comparing those patients with no or mild MR with those with moderate MR, this latter group showed higher end-diastolic (120 ± 37 versus 105 ± 29; p = 0.009) and end-systolic (87 ± 35 versus 71 ± 26; p = 0.031) indexed volumes. Using a propensity score analysis, a group of 70 patients with no or mild MR (group A) was case-matched with a group of 70 patients with moderate MR (group B) to obtain two groups with similar LV dilatation.

Table 1 shows the preoperative characteristics of the two groups. Patients were similar except for the mean New York Heart Association (NYHA) class and the mean degree of MR, both higher in group B.


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  		Table 1. Preoperative Characteristics
 
Surgical Technique
In 84 patients (60.0%), the procedure was performed on-pump (41 [58.5%] in group A; 43 [61.4%] in group B; not significant), whereas in the remaining 56 the procedure was performed off-pump. Fourteen patients (10.0%) had a left anterior small thoracotomy operation (8 [11.4%] in group A; 6 [8.6%] in group B; not significant). Details of the surgical technique have been reported [26].

Clinical Data Collection, Monitoring, and Definition
A set of perioperative data was collected prospectively for all patients undergoing CABG at our institution. The following were recorded and defined. Mortality included death of any cause. Cardiac mortality included any death for cardiac causes and sudden deaths. Cerebral vascular accident was defined as global or focal neurologic deficit, diagnosed by a neurologist and confirmed by a brain computed tomographic scan. Acute myocardial infarction was defined as enzymatic elevation, electrocardiographic sign of necrosis, new akinetic segment(s) at echocardiogram, or ventricular arrhythmias that were not potassium related. Early negative primary end point was defined as the sum of death of any cause, acute myocardial infarction, and cerebral vascular accident (each patient included only once).

Follow-Up
All the patients were followed up in our outpatient clinic at 3, 6, and 12 months after surgery and thereafter at yearly intervals. The most recent information was obtained by calling the patient or the referring cardiologist. Follow-up ended June 30, 2005, and was 100% complete.

Statistical Analysis
Results are expressed as mean ± standard deviation. Statistical analysis comparing the two groups was performed with unpaired two-tailed Student's t testing for the means or {chi}2 test for categorical variables. Stepwise logistic regression was used to realize a model to calculate the propensity score. Variables included in the stepwise logistic regression analysis are shown in the appendix. Each patient in group A was matched with the patient with the closest propensity score in group B. Eight-year actuarial results were obtained with the Kaplan–Meier method. Statistical significance was calculated with the log-rank test. Cox analysis was used to evaluate the independent risk factors for reduced late events. Independent variables were expressed as hazard ratio; the related p value was also reported. The SPSS software (Chicago, IL) was used. Values of p less than or equal to 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Number of anastomoses per patient was 2.6 ± 1.1, 2.5 ± 1.1 in group A and 2.7 ± 1.2 in group B (not significant). Only arterial grafts were used in 70 patients (50.0%), 32 (45.7%) in group A and 38 (54.2%) in group B (not significant). No patient had incomplete revascularization. Thirty-day outcome is shown in Table 2. There was no difference in the early results between groups.


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  		Table 2. Early Outcomes
 
After a mean of 33.5 ± 27.1 months, 50 patients died (17 in group A, 33 in group B), 40 of cardiac causes (12 in group A, 28 in group B). Fifteen patients had a new acute myocardial infarction (6 in group A, 9 in group B), 20 exhibited new ischemic symptoms (9 in group A, 11 in group B), and 28 (12 in group A, 16 in group B) were in NYHA class III or IV.

After a mean of 99.5 ± 25.0 months, 81 patients were alive. Figures 1 through 5 Go Go Go Go show the possibility to be free, 8 years after surgery, from death, cardiac death, ischemic events (acute myocardial infarction and angina), cardiac death and ischemic events, and death and NYHA class III or IV. Table 3 shows the results of Cox analysis. Moderate MR is an independent factor for lower freedom from death, cardiac death, cardiac death and ischemic events, and death and NYHA class III or IV.


Figure 1
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  		Fig 1. Possibility to be free from death according to preoperative mitral regurgitation: group A (solid line) and group B (dashed line).

 

Figure 2
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  		Fig 2. Possibility to be free from cardiac death according to preoperative mitral regurgitation: group A (solid line) and group B (dashed line).

 

Figure 3
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  		Fig 3. Possibility to be free from ischemic events according to preoperative mitral regurgitation: group A (solid line) and group B (dashed line).

 

Figure 4
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  		Fig 4. Possibility to be free from cardiac death and ischemic events according to preoperative mitral regurgitation: group A (solid line) and group B (dashed line).

 

Figure 5
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  		Fig 5. Possibility to be free from death and New York Heart Association class III or IV according to preoperative mitral regurgitation: group A (solid line) and group B (dashed line).

 

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  		Table 3. Cox Analysis
 
After a mean of 62 ± 28 months, 87.8% of the survivors (71 patients, 44 in group A, 27 in group B) had an echocardiographic evaluation in our laboratory. The remaining 10 patients did not accept to come to our institution. The results are reported in Table 4. In group A there was a favorable LV remodeling, showed by reduction of LV volumes and concomitant increase of ejection fraction; NYHA class in this group remained stable. In group B, on the contrary, volumes remained unchanged as well as ejection fraction, whereas functional class and MR worsened.


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  		Table 4. Functional and Echocardiographic Results
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Although Burch and colleagues [27] had already introduced the term ischemic cardiomyopathy in 1970, the World Health Organization in 1981 preferred to classify the cardiomyopathies into dilated, hypertrophic, and restrictive [28]. But, as recently demonstrated by Felker and associates [1], ischemic cardiomyopathy should be considered as isolated entity that is associated with a poorer outcome than a nonischemic one [29, 30]. In fact, it has been considered the main cause of heart failure, being the underlying cause in nearly 70% of patients with heart failure [3].

Ischemic cardiomyopathy can be defined as severe LV dysfunction as a result of sequelae of either acute myocardial infarction or chronic coronary artery disease [1]. Heart transplantation is advocated as the gold standard to treat this disorder, but, as it is well known, it presents several limitations (ie, shortage of donors, diabetes, irreversible high pulmonary resistances) that reduce its wide application [4]. In this scenario, myocardial revascularization has represented, for many years, a surgical alternative to treat ischemic cardiomyopathy. Therefore, during the last decade, many authors have focused their attention on clearly demonstrating the benefits of isolated CABG on long-term outcome of patients with ischemic cardiomyopathy [5–10, 15, 19, 21–24], but the problem still remains unsolved.

Most of these studies stated that CABG can improve prognosis and heart failure symptoms, and restore LV function, at least in those patients who showed viable myocardium [5–10] at one of the common myocardial viability testing procedures [11]. However, myocardial viability seems not to be the only predictor of myocardial recovery after isolated CABG. Schinkel and coworkers [12] recently reported that even if 52% of their patients with ischemic cardiomyopathy had substantial amount of viable myocardium, 33% of them did not show any improvement of LV function after isolated CABG. An explanation for this failure has been found in a higher end-systolic volume after LV remodeling. Maxey and coworkers [31] proposed ventricular restoration, to be added to CABG, as a valid option to restore the elliptical shape of the LV, achieving an important improvement of the ejection fraction. However, LV surgical restoration can be indicated just in cases of regional akinesia or dyskinesia.

Another important aspect to take in account when choosing the most appropriate surgical strategy for treatment of ischemic cardiomyopathy is the presence and the entity of MR. Ischemic MR is present in approximately 20% of patient with previous myocardial infarction [32], and it can be caused by annular dilation and global LV dilation with both papillary muscle displacement or single papillary muscle displacement with adjacent wall dysfunction. Mitral regurgitation has clearly been shown to affect the natural history of patients with previous myocardial infarction, especially in case of LV dysfunction [13, 14, 33].

In spite of these issues, there is no general agreement on the opportunity to treat moderate MR in patients with LV dysfunction. The role of isolated myocardial revascularization in the treatment of ischemic cardiomyopathy if moderate MR is present is still debated [15–24]. Hence, we decided to analyze retrospectively patients with ischemic cardiomyopathy who underwent isolated CABG to evaluate the impact of no-to-moderate MR on their long-term results. Our retrospective study compared two cohorts of patients with ischemic cardiomyopathy. The first group showed no or mild MR, whereas the second group included patients with moderate MR.

Survival and Quality of Life
Cox analysis demonstrated that the presence of moderate MR is an independent variable that can impair significantly survival, freedom from cardiac death, freedom from cardiac events (cardiac deaths, ischemic events), and quality of life (possibility to be free from death and NYHA class III or IV) in patients with ischemic cardiomyopathy. Furthermore, preoperative clinical status (NYHA class, heart failure) and age of patient represent important predictors of worse late outcome, confirming the findings reported by DeRose and associates [34].

Our results are consistent with the study from Mallidi and colleagues [22]. These authors studied a cohort of 489 patients, comparing 6-year outcome of 163 of them with 2+ ischemic MR versus 336 without MR. Although they failed to demonstrate any impact of MR on late survival, they found a significant difference concerning event-free survival between the two groups (64.7% no MR versus 36.8% MR). The analysis of late functional status by severity of MR showed that 23.5% of patients with preoperative moderate MR had NYHA class III or IV versus 10.5% in group MR 1+ and 8.1% in group MR 0 (p = 0.0042). In our group of patients, NYHA class III or IV was present in 17.1% of group A and in 55% of group B (p = 0.001).

The impact of any degree of MR on long-term results is continuously investigated. Schroder and coworkers [35] demonstrated that mild or moderate MR, detected during surgery using transesophageal echocardiography, predicted worse outcome after isolated CABG. Revascularization alone did not eliminate the negative long-term effects of mild or moderate MR. These patients were at increased risk for lower survival and higher incidence of hospitalization for heart failure.

The reason may be, in agreement with Levine and Schwammenthal [36], the intrinsic capacity of MR, caused by altered geometry and function as a consequence of ischemic heart disease, to initiate remodeling. Mitral regurgitation alters LV loading; it increases diastolic wall stress, which can induce LV dilation and failure, and end-systolic wall stress, with decreased contractility and increased end-systolic volume. Increased wall stress can aggravate remodeling by activating metalloproteinases, which degrade extracellular matrix [37], and increasing neurohormonal and cytokine promoters of remodeling, driving a vicious circle in which MR begets MR. When we, as surgeons, should interfere with this mechanism is today not clear; however, there is a supporting body of evidence that moderate MR can impair long-term prognosis of patients with ischemic heart disease.

Echographic Results
Of 81 survivors, 71 patients (87.8%) underwent an echocardiographic control about 5 years after surgery. Even if ejection fraction improved significantly after myocardial revascularization, this improvement was limited to group A, in which the degree of MR remained unchanged. Concomitantly, there was a reduction of systolic and diastolic volumes. On the contrary, in group B MR increased significantly, and volumes and ejection fraction remained unchanged. These findings can explain why NYHA class remained stable in group A and worsened in group B.

In our series, CABG alone was not able to stabilize moderate MR [21], but only no or mild MR. On the contrary, preoperative moderate MR worsened with increasing postoperative years. This difference of findings is not explained by a higher grade of LV remodeling that is often present in patients with ischemic cardiomyopathy, and which is the anatomic base for MR development, as we selected patients with similar LV volumes. Our results are another demonstration that CABG alone is not able to reverse or to stabilize MR when it is moderate or of higher degree.

Our observations were confirmed by other studies. Harris and colleagues [15] compared two groups of patients with moderate MR who underwent CABG alone or CABG plus mitral valve surgery. They found that CABG alone did not avoid early progression of MR to more severe degrees, and this especially in patients with heart failure and low ejection fraction. In another report [19], of 49 patients controlled at 16 months, 31% of cases showed an increase of MR of at least one degree.

The main limitation of this research is the relatively small number of patients and the retrospective character of the study. Analysis of myocardial viability was inconstant in time and for this reason was not included in this study.

There is a vast literature concerning the role of myocardial revascularization in treatment of ischemic cardiomyopathy, but none of these studies was aimed at evaluating the impact of uncorrected moderate MR on patients with LV dysfunction who underwent CABG alone. The option of intervention on moderate ischemic MR is still "the bone of contention" among the surgeons. This study confirms that moderate ischemic MR has an important negative impact on either survival or quality of life of patients with severely impaired LV function whenever they are treated by CABG alone.

Our data do not allow us to demonstrate that the outcome of these patients would be better after treatment of moderate MR, but, the prognosis of these patients being poor, we believe that it is reasonable to give them a surgical option other than CABG alone. Treatment of MR can be a reasonable alternative.


   Appendix
 
List and Definition of the Variables Included in the Stepwise Logistic Regression


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   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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M. Di Mauro, A. M. Calafiore, M. Penco, S. Romano, G. Di Giammarco, and S. Gallina
Mitral valve repair for dilated cardiomyopathy: predictive role of right ventricular dysfunction
Eur. Heart J., October 2, 2007; 28(20): 2510 - 2516.
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 ICVTSHome page
A. R. Srivastava, A. Banerjee, S. Jacob, and J. Dunning
Should patients undergoing coronary artery bypass grafting with mild to moderate ischaemic mitral regurgitation also undergo mitral valve repair or replacement?
Interactive CardioVascular and Thoracic Surgery, August 1, 2007; 6(4): 538 - 546.
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 Ann. Thorac. Surg.Home page
U. Sartipy, A. Albage, E. Mattsson, and D. Lindblom
Edge-to-Edge Mitral Repair Without Annuloplasty in Combination With Surgical Ventricular Restoration
Ann. Thorac. Surg., April 1, 2007; 83(4): 1303 - 1309.
[Abstract] [Full Text] [PDF]

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