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Ann Thorac Surg 2005;80:811-819
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Ischemic Versus Degenerative Mitral Regurgitation: Does Etiology Affect Survival?

^a Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
^b Department of Biostatistics and Epidemiology, The Cleveland Clinic Foundation, Cleveland, Ohio
^c Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio

Accepted for publication March 16, 2005.

^_* Address reprint requests to Dr Gillinov, The Cleveland Clinic Foundation, 9500 Euclid Avenue / Desk F24, Cleveland, OH 44195 (Email: gillinom{at}ccf.org).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
BACKGROUND: Ischemic mitral regurgitation (MR) is associated with poor survival and degenerative MR with excellent survival. We hypothesized that in some patients with degenerative MR requiring concomitant coronary artery bypass grafting (CABG), ischemic disease would dominate prognosis, resulting in survival as poor as in patients with ischemic MR. Thus, we (1) determined survival impact of etiology (degenerative vs ischemic) after combined mitral valve repair and CABG and (2) explored survival differences within etiology groups.

METHODS: From 1985 to 2003, 710 patients underwent mitral valve repair for degenerative MR and concomitant CABG (two diseases); 400 patients had mitral annuloplasty and CABG for functional ischemic MR (one disease). Patients were propensity-matched on demography, symptoms, comorbidities, coronary artery disease, and left ventricular function. Survival was compared between matched groups and within groups.

RESULTS: Compared with patients with degenerative MR, those with ischemic MR had more extensive coronary artery disease, worse ventricular function, more comorbidities, and more symptoms (p < 0.05). Unadjusted 5-year survivals were 64% and 82% for patients with ischemic and degenerative MR, respectively. However, 123 ischemic and degenerative MR matched pairs had equivalently poor 5-year survival (p > 0.9), 66% and 65%, respectively. Among patients with degenerative MR, survival varied widely, depending largely on ischemic burden and extent of left ventricular dysfunction.

CONCLUSIONS: The large survival discrepancy between patients with ischemic and degenerative MR is attributable to differences in patient profile, particularly extent of ischemic disease and left ventricular dysfunction. Thus, ischemic and degenerative MR patients with equivalent characteristics have equivalently poor survival.

	Introduction

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Operations that include both mitral valve surgery and coronary artery bypass grafting (CABG) have been associated with high hospital mortality and limited long-term survival [1–9]. However, most studies of these procedures contain heterogeneous patient groups, making it difficult to isolate the impact of mitral valve disease etiology on survival when mitral valve dysfunction and coronary artery disease coexist [4, 6, 9]. In general, ischemic mitral regurgitation (MR) is associated with poor survival and degenerative MR with excellent survival [1–4, 10–12]. We hypothesized that in some patients with degenerative MR requiring concomitant CABG, ischemic disease would dominate prognosis, resulting in survival as poor as in patients with ischemic MR. Thus, we (1) isolated the survival impact of etiology (degenerative vs ischemic) after combined mitral valve repair and CABG and (2) explored survival differences within etiology groups.

	Patients and Methods

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Definitions
Mitral regurgitation was judged to be of ischemic etiology when valve leaflets and chordae appeared normal and MR was caused by consequences of a myocardial infarction; all patients with ischemic MR had at least one previous myocardial infarction, based on standard criteria extracted from review of clinical information, echocardiograms, and direct surgical inspection [1, 2, 10, 11, 13]. Those with normal-appearing papillary muscles, chordae, and leaflets were classified as having functional ischemic MR and were included in this study. Their leaflets failed to coapt, and echocardiograms frequently demonstrated restricted leaflet motion (Carpentier type IIIb leaflet motion) [11–13].

Mitral regurgitation was judged to be of degenerative etiology if microscopic pathologic examination of resected leaflet material revealed myxomatous degeneration, although we recognize that myxoid material might represent a final common pathway for possible diverse causes. When pathology reports were unavailable, valves were classified as degenerative if on echocardiography or direct surgical inspection they had typical findings of leaflet prolapse caused by chordal elongation or rupture and thick, floppy leaflets [12]. Finally, those rare patients with annular dilatation and thick billowing leaflets, but without frank prolapse, were judged to have degenerative disease.

Study Group
Using these definitions, patients undergoing mitral valve repair from 1985 to 2003 who could potentially be included in this study were identified by query of the Cardiovascular Information Registry. This registry contains detailed demographic, clinical, pathologic, operative, and outcome variables on all patients undergoing cardiac surgery at The Cleveland Clinic Foundation, abstracted from clinical records concurrent with patient care. The registry is approved for use in research by the Institutional Review Board.

Because definitions of etiology of valve dysfunction have evolved, and because of the need to clearly separate degenerative disease from ischemic disease, search criteria were intentionally broad to cast a wide net that we believed would capture all instances of mitral valve repair in the settings of degenerative disease with CABG and functional ischemic MR. Medical records of the 2,000 patients so identified were reviewed to verify etiology, netting 1,110 patients; 710 had mitral valve repair for degenerative MR with concomitant CABG (two diseases), and 400 had mitral annuloplasty for functional ischemic MR and CABG (one disease). All had at least 2+ (moderate) MR. Patients undergoing concomitant tricuspid valve repair were included, but those undergoing aortic valve or Maze procedures or reoperations were not.

Mean patient age of the entire group was 68 ± 9 years. Patients with ischemic MR had more extensive coronary artery disease, more severe left ventricular dysfunction, higher New York Heart Association (NYHA) functional class, and more severe noncardiac comorbidity (Table 1). Patients with degenerative mitral valve disease had more severe MR.

Follow-Up
Patients were followed systematically at two-year intervals by means of a mailed questionnaire, telephone interview, or examination at the Cleveland Clinic. Data regarding vital status were augmented using the Social Security Death Index. Median follow-up durations for degenerative and ischemic groups were 4.1 years and 3.1 years, respectively. This yielded 3,766 patient-years of follow-up for the degenerative group and 1,480 years for the ischemic group. Among propensity- matched patients with ischemic or degenerative MR (123 in each group), median follow-up was 2.6 years in the degenerative group and 3.2 years in the ischemic group, yielding totals of 484 and 443 patient-years of follow-up, respectively. Survival estimates were considered reliable to at least 9 years.

Data Analysis
Unadjusted survival
Unadjusted survival estimates between and within etiology groups were obtained using the nonparametric Kaplan-Meier method and a parametric method that resolved phases of instantaneous risk (hazard) [15]. (For additional details, see http://www.clevelandclinic.org/heartcenter/hazard.)

Propensity matching and comparatives survival
Propensity matching was used to assess the effect of etiology of mitral valve dysfunction on survival [16, 17]. Logistic regression analysis was used to identify demographic, clinical, comorbid, and coronary disease factors associated with ischemic versus degenerative etiology (Appendix). To these were added nonsignificant variables for each of the above classes of factors (saturated model), 61 variables in all. Patients with ischemic and degenerative etiologies were then matched on propensity score for variables used in the analysis, yielding 123 propensity-matched pairs (Table 2). Survival was compared between these matched ischemic MR and degenerative groups, and also between matched versus unmatched ischemic MR patients, and matched versus unmatched degenerative disease groups (Tables 3 and 4).

	Results

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
Unadjusted Survival
Hospital mortality was 3.1% (22/710, CL 2.4% and 3.9%) in patients with degenerative mitral disease and 5.0% (20/400, CL 3.9% and 6.4%) in those with ischemic MR. Unadjusted 5-year survival was 82% in the degenerative group versus 64% in the ischemic MR group (p [log-rank] < 0.0001; Fig 1).

View larger version (23K): [in this window] [in a new window]   Fig 1. Unadjusted survival after mitral valve repair and coronary artery bypass grafting in patients with ischemic mitral regurgitation or degenerative mitral valve and coronary artery diseases. (A) Survival. Each symbol represents a death positioned on the vertical axis by the nonparametric Kaplan-Meier estimator, vertical lines are asymmetric 68% confidence limits (equivalent to +1 standard error), and numbers in parentheses are patients still alive and traced. Solid lines are parametric estimates enclosed within 68% confidence limits. Ischemic mitral regurgitation is represented by squares and degenerative mitral regurgitation by circles. (B) Instantaneous risk of death (hazard function). Dashed lines enclose 68% confidence limits.

View larger version (23K): [in this window] [in a new window]   Fig 2. Survival after mitral valve repair and coronary artery bypass grafting in propensity-matched patients with ischemic and degenerative mitral regurgitation (123 patients in each group). (A) Survival. Each symbol represents a death positioned on the vertical axis by the nonparametric Kaplan-Meier estimator, vertical lines are asymmetric 68% confidence limits (equivalent to +1 standard error), and numbers in parentheses are patients still alive and traced. Solid lines are parametric estimates enclosed within 68% confidence limits. Ischemic mitral regurgitation is represented by squares and degenerative mitral regurgitation by circles. (B) Instantaneous risk of death (hazard function). Dashed lines enclose 68% confidence limits.

View larger version (22K): [in this window] [in a new window]   Fig 3. Survival after mitral valve repair and coronary artery bypass grafting in matched and unmatched patients with ischemic mitral regurgitation. Each symbol represents a death positioned on the vertical axis by the nonparametric Kaplan-Meier estimator, vertical lines are asymmetric 68% confidence limits (equivalent to +1 standard error), and numbers in parentheses are patients still alive and traced. Solid lines are parametric estimates enclosed within 68% confidence limits. Ischemic mitral regurgitation is represented by squares and degenerative mitral regurgitation by circles.

View larger version (24K): [in this window] [in a new window]   Fig 4. Survival after mitral valve repair and coronary artery bypass grafting in matched and unmatched patients with degenerative mitral regurgitation. Each symbol represents a death positioned on the vertical axis by the nonparametric Kaplan-Meier estimator, vertical lines are asymmetric 68% confidence limits (equivalent to +1 standard error), and numbers in parentheses are patients still alive and traced. Solid lines are parametric estimates enclosed within 68% confidence limits. Ischemic mitral regurgitation is represented by squares and degenerative mitral regurgitation by circles.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Discussion References

Ischemic Mitral Regurgitation
The poor long-term survival [1, 2, 10, 18, 19] seen in patients with coronary artery disease and ischemic MR is associated with a graded effect: the greater the degree of MR, the lower the survival [20, 21]. Recognizing the deleterious impact of ischemic MR, surgeons have studied this entity intensely over the last decade [1–9, 11, 13, 18, 19]. With improved understanding of its pathogenesis and advances in surgical and perioperative management, hospital mortality has been reduced from 10% or greater to 2%–7% [1, 11, 18].

The most common type of ischemic MR is functional ischemic MR. In this condition, myocardial infarction and subsequent remodeling cause changes in ventricular and annular geometry that prevent leaflet coaptation, resulting in a jet of MR that is usually directed centrally or posteriorly [1, 10, 22]. It is generally accepted that mitral valve repair is superior to replacement for this entity, with repair usually consisting of annuloplasty alone [1, 2, 10, 13]. Although mitral valve repair is technically successful in the majority of these patients, long-term survival is limited [1–4]. The most important determinants of mortality include advanced age, reduced left ventricular function, and higher NYHA functional class [1–10]. Patients with functional ischemic MR represent a relatively homogeneous group with respect to these factors, which explains the equivalent survival curves of matched and unmatched ischemic MR patients (see Fig 3). These similarities in patient presentation and outcome in ischemic MR distinguish this entity from other etiologies of MR.

Degenerative Mitral Valve Disease
In contrast to patients with ischemic MR, those with coexisting degenerative mitral valve disease and coronary artery disease have two diseases; our findings suggest that in such patients, variable severity of coronary artery disease and, secondly, left ventricular dysfunction, have a major impact on long-term survival.

There is a wide spectrum of cardiac comorbidity in patients presenting for surgical correction of degenerative mitral valve disease. Those with isolated degenerative mitral valve disease present for surgical repair at a mean age of 58 ± 12 years; most have normal left ventricular function, and 84% are in NYHA functional class I or II [12]. Hospital mortality is less than 1%, and 5-year and 10-year survivals are greater than 90% and 80%, respectively [12, 23, 24]. In contrast, patients with degenerative mitral valve disease and coexisting coronary artery disease have more variable clinical presentations and outcomes, which explain the different survival curves between matched and unmatched patients (see Fig 4). As in ischemic MR, long-term survival is modulated by patient age, extent of left ventricular dysfunction, and NYHA functional class [14].

Impact of Etiology on Survival
There are few data comparing outcomes in these two groups of patients with both mitral valve dysfunction and coronary artery disease. In a review from the Mayo Clinic, Dahlberg and colleagues [3] studied 302 patients undergoing mitral valve repair or replacement and CABG; approximately half had ischemic MR and half had degenerative mitral valve disease. As in our study, patients with ischemic disease tended to have more left ventricular dysfunction, more extensive coronary artery disease, and higher NYHA functional class. Unadjusted 10-year survivals were 33% in the ischemic group and 52% in the degenerative group. Advanced age, reduced left ventricular function, and extent of coronary artery disease influenced survival; etiology of mitral valve dysfunction was not an independent risk factor. Like us, they concluded that survival after mitral valve surgery and CABG is determined primarily by extent of coronary artery disease and left ventricular dysfunction rather than by etiology of the mitral valve disease. The sequence of myocardial infarction and remodeling associated with ischemic MR has a greater impact on survival than does the degree of MR.

Others [4, 5, 25] have also noted important preoperative differences between patients with ischemic MR and those with combined degenerative MR and coronary artery disease. Glower and colleagues [25] found that etiology of mitral dysfunction was not an independent predictor of survival; rather, advanced age and comorbidities determined long-term survival. Similarly, Bouchard and colleagues [5] noted that in patients undergoing mitral valve replacement and CABG, comorbidities, not etiology of valve dysfunction, affected late survival.

Limitations
There were important preoperative differences between patients with ischemic and degenerative MR (Table 1). By using propensity matching, we attempted to adjust for survival differences in patient characteristics (Table 2); however, it is possible that other, unrecorded variables also influenced outcomes.

In this report, we have not addressed the issue of durability of mitral valve repair. This topic has been studied extensively and reported in previous publications [1–3, 12, 13, 23, 24, 26, 27].

We cannot address in a formal fashion the relationship between progression of postoperative MR and survival. Others have suggested that MR recurrence jeopardizes survival [3]; however, to our knowledge, statistical methodology to properly test this hypothesis does not exist because both recurrent MR and death are outcomes of surgery. Examination of their interdependence and their relationship to surgical technique requires developing novel statistical methodology.

Clinical Inferences
Patients with functional ischemic MR represent a relatively homogeneous group with limited postoperative survival. In contrast, patients with degenerative mitral valve disease and coronary artery disease have two distinct diseases; in these patients, extent of ischemic disease and resulting left ventricular dysfunction are critical determinants of long-term survival. Thus, the sequence of myocardial infarction and subsequent remodeling has a greater impact upon survival than does the degree of MR. This suggests that strategies to prevent or reverse the remodeling sequence associated with the development of ischemic MR may be important components of future efforts to manage this condition.

	Appendix

 
Variables Used in Analysis

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Discussion References

DR GILLINOV: We have performed follow-up on these patients, although it is not presented as a component of this paper. As you know, in the patients with degenerative mitral valve disease, the long-term freedom from reoperation and recurrent mitral regurgitation is excellent, more than 90% at 10 years, and in recent studies, similar figures at 20 years. In patients with functional ischemic mitral regurgitation, the results are not as good. Up to a third of the patients with ischemic MR (mitral regurgitation) treated in our series with various types of annuloplasty, developed mitral regurgitation that was 2+ or greater over the first postoperative year.

You raise the question, can we relate recurrent mitral regurgitation to survival, and the answer is that we cannot. Others have attempted to show a relationship between these two outcomes, but in truth the statistical methodology to demonstrate that one outcome has an impact on another outcome—namely, that mitral regurgitation reduces survival—that methodology doesn’t exist. On the other hand, it does make clinical sense to suppose that the more recurrent mitral regurgitation a patient has, the worse the clinical outcome. However, testing this hypothesis is challenging.

DR LISHAN AKLOG (New York, NY): I enjoyed your presentation. It was, as usual, a very elegant statistical analysis. I wouldn’t quibble with the data or the analysis of the data but I am having a hard time understanding the message specifically. That is because the number of patients that you were able to match each group was relatively small. By my math, about a third of the ischemic patients and about a fifth of the degenerative patients were ultimately matched. That left a large number of unmatched patients in both groups. So what is the real message for us out there in treating these two diseases given that your analysis was based on fairly select subgroups?

You said that the unmatched and matched patients in the ischemic group were fairly similar. If they were fairly similar, why was such a small fraction ultimately able to be entered in the propensity matching analysis? And who are these patients in the degenerative group that do poorly? What are their characteristics?

DR GILLINOV: The message is that patients who have both degenerative mitral valve disease and coronary artery disease span a wide spectrum of clinical presentations; just because somebody has coronary disease and mitral valve dysfunction does not mean that they are going to have a poor outcome. Amongst patients with ischemic mitral regurgitation, the outcomes are generally pretty poor. But if you go to operate on a patient who needs bypass grafting and a mitral valve procedure, that patient, if he has degenerative disease, may do very well. So I think that is one of the primary messages.

The reason we could not match every degenerative patient is that we did not have enough ischemic patients who had favorable clinical features, meaning good left ventricular function, less coronary artery disease, and fewer comorbidities.

	References

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 

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