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Mitral regurgitation in patients with advanced systolic heart failure
Journal of Cardiac Failure Vol. 10 No. 4 2004
Mitral Regurgitation in Patients With Advanced Systolic Heart Failure JEETENDRA B. PATEL, MD,1 DANIEL D. BORGESON, MD,1 MARION E. BARNES,1 CHARANJIT S. RIHAL, MD,1 RICHARD C. DALY, MD,2 AND MARGARET M. REDFIELD, MD1 Rochester, Minnesota
ABSTRACT Background: Mitral regurgitation (MR) may develop in patients with advanced systolic congestive heart failure (CHF) without organic mitral valve disease and contribute to worsening symptoms and survival. Surgical mitral annuloplasty improves symptoms in patients with advanced CHF, and percutaneous approaches to mitral annuloplasty are being developed. Our objective was to define the prevalence, clinical correlates, and prognostic implications of functional MR and the use of mitral annuloplasty in patients with advanced systolic CHF evaluated in a heart failure clinic. Methods and Results: We reviewed clinical, echocardiographic, and survival data from all patients with advanced systolic CHF (New York Heart Association class III or IV; ejection fraction ⱕ35%) resulting from ischemic or idiopathic cardiomyopathy who were evaluated at our heart failure clinic between January 1996 and September 2001. Of 716 patients with advanced CHF, 558 had satisfactory baseline echocardiograms performed at our institution. Among these patients, MR was severe in 24 (4.3%), moderate-severe in 70 (12.5%), moderate in 122 (21.9%), mild-moderate in 66 (11.8%), mild in 218 (39.1%), and absent or present as only a trace in 58 (10.4%). The severity of MR was confirmed by quantitative analysis in 72% of patients with hemodynamically significant MR (more than moderate). The severity of MR correlated with the severity of systolic dysfunction (P ⬍ .001), ventricular dilatation (P ⬍ .03), atrial dilatation (P ⬍ .001), diastolic dysfunction (P ⬍ .001), and pulmonary hypertension (P ⬍ .001). Coexistent severe or moderate-severe tricuspid regurgitation was present in 25% of patients with hemodynamically significant MR. Patients with hemodynamically significant MR had higher mortality (P ⫽ .03) but not when controlling for age, sex, cause, New York Heart Association class, and ejection fraction (P ⫽ .95). Only 3 patients subsequently underwent mitral valve repair. Conclusion: Among patients with advanced CHF, hemodynamically significant MR is common. The severity of MR did not provide independent prognostic information in this group recognized to have uniformly high mortality. Key Words: Congestive heart failure, Prognosis, Tricuspid valve regurgitation.
Congestive heart failure (CHF) is a common, costly, lethal syndrome that affects an estimated 4.7 million Americans, with 550,000 new cases diagnosed annually.1 As many as 25% of these patients has advanced disease (New York Heart Association [NYHA] class III or IV).2 Treatment strategies for advanced CHF are limited.
Mitral regurgitation (MR) may develop in patients with severe systolic dysfunction and left ventricular dilatation without organic mitral valve disease (ie, functional MR). Hemodynamically significant MR (HSMR) may exacerbate the hemodynamic strain on the failing left ventricle, contributing to worsening symptoms and survival. Indeed, in previous studies, MR was associated with increased cardiovascular mortality among unselected patients with prior myocardial infarction3,4 or systolic dysfunction5–7 identified from echocardiographic, catheterization, or clinical trial databases. Surgical mitral annuloplasty improves symptoms in patients with advanced CHF,8–11 and percutaneous approaches to mitral annuloplasty are being developed for treatment of functional MR in CHF.12 The effect of mitral annuloplasty on survival is unclear, but initial data suggest that correction of MR may improve survival for patients with advanced CHF.8–11 However, the number of patients potentially eligible
From the Divisions of 1Cardiovascular Diseases and Internal Medicine and 2Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota. Manuscript received June 23, 2003; revised manuscript received December 15, 2003; revised manuscript accepted December 19, 2003. Reprint requests: Margaret M. Redfield, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Funding by Marriott Foundation, Miami Heart Research Institute, Mayo Foundation, and the National Institutes of Health (T32-HL07111-27). 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2003.12.006
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for surgical or percutaneous annuloplasty is unclear because there are few data on the prevalence of functional MR in patients with advanced CHF. The objective of this study was to define the prevalence, clinical and echocardiographic correlates, and prognostic implications of functional MR in patients with advanced systolic CHF evaluated in the heart failure clinic at our tertiary referral center. Further, we sought to determine the current use of mitral valve repair as therapy for advanced CHF at our institution. Methods Study Population The Mayo Foundation Institutional Review Board approved this study. Mayo Clinic maintains a database of all patients initially evaluated at the Mayo Clinic Heart Failure Clinic since its inception in 1991. The data include demographic characteristics, severity of CHF (NYHA class), cause of ventricular dysfunction, and ejection fraction (EF). We selected patients who had advanced symptoms (NYHA class III or IV) and reduced systolic function (EF ⱕ35%) resulting from ischemic or idiopathic dilated cardiomyopathy. The diagnosis of ischemic or idiopathic cardiomyopathy was made by the heart failure clinician after the initial comprehensive evaluation and review of all pertinent laboratory tests, which typically included perfusion imaging, confirmation of previous history of myocardial infarction, or angiography. This impression was entered in the heart failure database. We excluded patients whose echocardiograms were not performed at Mayo Clinic, patients with inadequate or incomplete echocardiograms, and patients with organic mitral valve disease (mitral stenosis, mitral prolapse, or rheumatic or degenerative MR) that was identified at echocardiography. To increase the percentage of patients in whom the severity of MR was confirmed by quantitative analysis, our study was restricted to patients identified between January 1, 1996, and September 14, 2001, because routine quantitative assessment of MR was incorporated into our echocardiographic laboratory in the first half of the 1990s. Patients who had prior or subsequent mitral valve procedures or cardiac transplantation at Mayo Clinic were identified by reference to the cardiac surgical database and the medical record. Echocardiography Left ventricular end-diastolic, left ventricular end-systolic, and left atrial dimensions were obtained by M-mode echocardiography guided by 2-dimensional imaging. EF was measured by M-mode, 2-dimensional, or semiquantitative visual estimate, and the value for EF was used unaltered from the echocardiographic report as previously reported.3,13 The presence of organic mitral valve disease was assessed by 2-dimensional imaging of the mitral valve, and the existence of several features was sought: mitral valve prolapse, flail mitral valve leaflet, prosthetic mitral valve, and rheumatic or degenerative mitral valve thickening or calcification. Data on the severity of MR were entered unaltered from the echocardiographic report by electronic transfer. Routine assessment of MR in our echocardiographic laboratory incorporates semiquantitative methods (color flow imaging and pulmonary venous flow pulsed wave Doppler integration) and quantitative methods (quantitative Doppler and proximal isovelocity surface area [PISA]). The severity of MR was graded according to the following scale: trace/no, mild, mildmoderate, moderate, moderate-severe, or severe. The severity of
MR was also characterized according to proposed hemodynamic significance and was described as being HSMR (severe, moderatesevere, or moderate) or hemodynamically nonsignificant MR (NHSMR) (mild-moderate, mild, or trace/no), as previously described.3 Although use of the PISA method is recommended for calculating the regurgitant volume and estimated regurgitant orifice (ERO) in the routine assessment of MR in our laboratory, it was not performed or was not possible to perform for all patients. Severity of tricuspid valve regurgitation was assessed by use of color flow imaging and color flow and pulsed-wave Doppler interrogation of the hepatic veins and was graded similarly to severity of MR. Pulmonary artery systolic pressure was estimated by measurement of the tricuspid regurgitation velocity and estimation of the right atrial pressure on the basis of imaging of the inferior vena cava, as previously described.14 Diastolic function was assessed by measurement of the early (E) and late (A) mitral inflow velocities, the E/A ratio, and the E deceleration time as measured by pulsed-wave Doppler.15 Survival Data The dates of death of the patients who died during the followup period were determined using the Social Security Death Index (available at commercial genealogy Web sites [eg, www.ancestry. com]) as of August 31, 2002. Follow-up data were unavailable for 12 patients for whom the Social Security number was not recorded. After the exclusion of 3 patients who underwent mitral valve repair or replacement during the follow-up period, 543 patients were included in survival analysis. For the purpose of the survival analysis, for the 4 patients receiving a cardiac transplant, the date of transplantation was considered to be the date of death. All patients receiving a transplant were classified as United Network for Organ Sharing status I at the time of transplantation. Statistical Analysis Continuous variables were expressed as mean ⫾ standard deviation (SD). Group comparisons between MR grades were performed by analysis of variance (Kruskal-Wallis test). The correlation between MR severity and clinical or echocardiographic variables was assessed by calculation of Spearman rank correlation coefficients. The survival rate free of all causes of death was estimated using the Kaplan-Meier method, and the association with MR severity and other variables was assessed using the log-rank test. The Cox proportional hazards regression model was used to adjust the association of MR or tricuspid regurgitation severity with allcause mortality for age, sex, NYHA class, EF, and cause of ventricular dysfunction. Analyses were performed using GraphPad Prism version 3.0 for Windows (GraphPad Software, San Diego, California) or JMP software (SAS Institute Inc, Cary, North Carolina).
Results Patient Characteristics
During the study period, data for 3357 new patients were entered in the Mayo Clinic Heart Failure Clinic database. Data for 3336 patients included a cause, NYHA class, and EF. A total of 716 patients had NYHA class III or IV CHF and EF ⱕ35% related to ischemic or idiopathic dilated cardiomyopathy. Of these, 608 had an echocardiogram at Mayo Clinic at the time of their heart failure clinic evaluation. Patients
Mitral Regurgitation in Heart Failure
with incomplete or inadequate echocardiograms (n ⫽ 33) or previous mitral valve surgery (n ⫽ 17) were excluded from analysis, leaving 558 patients in the study group. Of these, 3 patients had mitral valve surgery subsequent to the heart failure clinic evaluation and were excluded from the survival analysis, and 4 patients had cardiac transplantation subsequent to the heart failure clinic evaluation. None of the 558 patients selected in this manner were identified as having organic mitral valve disease at echocardiography. Of the patients excluded because they had mitral valve surgery before evaluation at the heart failure clinic, 11 had mitral valve repair or replacement for organic valve disease and 6 had annuloplasty or replacement with no evidence of organic valve disease at the time of bypass grafting (n ⫽ 4) or aneurysmectomy (n ⫽ 2). Of those patients who had mitral valve surgery subsequent to their referral to the heart failure clinic, 2 had annuloplasty at the time of bypass grafting and 1 had annuloplasty at the time of aortic valve replacement for lowoutput, low-gradient aortic stenosis associated with ischemic cardiomyopathy. Table 1 shows the prevalence of the grades of MR in patients with advanced CHF and the characteristics of patients according to the severity and hemodynamic significance of the MR. There was no statistically significant association between MR severity and age, body surface area, sex, or cause (ischemic or idiopathic). The mean NYHA class correlated with the severity of MR (r ⫽ .127, P ⫽ .002). Most patients were male. The frequency of pertinent risk factors in the different groups is also shown. The echocardiographic characteristics of patients with MR are shown in Table 2. The severity of systolic dysfunction, left ventricular and atrial dilatation, diastolic dysfunction, and pulmonary hypertension all correlated with the severity of MR. Quantitative Assessment of MR
Table 3 shows the results of quantitative assessment of the severity of MR with PISA. The frequency with which PISA measurements were performed increased with the severity of the MR. Among patients with HSMR, 72% had
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PISA performed. The average ERO and regurgitant volume correlated strongly with the assigned MR grade. The percentage of patients with severe or moderate-severe tricuspid regurgitation was higher among patients with more severe MR (Table 4). Fifty percent of patients with severe MR and 25% of patients with HSMR had either severe or moderate-severe tricuspid regurgitation. MR and Prognosis in Advanced CHF
Kaplan-Meier survival curves are shown in Fig. 1 for the entire study group and for patients according to the severity of MR by grade, MR designation as HSMR or NHSMR, and ERO. Mean survival time (⫾ SD), median survival, and the 1-, 2-, 3-, and 5-year survival rates are shown in Table 5. Mean survival time was shorter for patients with HSMR (1101 ⫾ 60 days) than for those with NHSMR (1257 ⫾ 48 days) (χ2 ⫽ 4.5; P ⫽ .03). However, in multivariate analysis controlling for age, sex, cause, NYHA functional class, and EF, the severity of MR was not an independent predictor of overall survival (Table 6). When only patients with quantitative assessment of MR (n ⫽ 216) were considered and grouped according to an ERO ⱖ0.20 cm2 or an ERO ⬍0.20 cm2, mean survival time was similar between the 2 groups (1051 ⫾ 71 days and 1136 ⫾ 60 days, respectively) (χ2 ⫽ .47; P ⫽ .49). These findings were similar when patients with ischemic or idiopathic causes were considered separately (Table 6). In multivariate analysis, the cause of ventricular dysfunction was the most important predictor of survival. The mean survival time among patients with advanced CHF resulting from idiopathic cardiomyopathy was 1495 ⫾ 53 days, as compared with 958 ⫾ 48 days among patients with advanced CHF resulting from ischemic cardiomyopathy (P ⬍ .0001). Although the severity of MR was weakly associated with mortality, the severity of tricuspid regurgitation more strongly correlated with outcome in univariate analysis (χ2 ⫽ 18.8; P ⫽ .002). In multivariate analysis controlling for age, sex, NYHA class, cause, and EF, the severity of tricuspid regurgitation tended to be an independent predictor of mortality (χ2 ⫽ 10.5; P ⫽ .06).
Table 1. Patient Characteristics According to Severity and Hemodynamic Significance of Mitral Regurgitation Characteristic No. of patients (%) Mean age ⫾ SD, y Mean body surface area ⫾ SD, m2 Male, % NYHA class IV, % Ischemic cause, % Diabetes, % Hypertension, % Smoking, % Hyperlipidemia, % Atrial fibrillation, %
Severe
Moderate-Severe
Moderate
Mild-Moderate
Mild
Trace/No
HSMR
NHSMR
24 (4.3) 70 ⫾ 7 1.94 ⫾ 0.23
70 (12.5) 68 ⫾ 11 1.89 ⫾ 0.23
122 (21.9) 70 ⫾ 10 1.93 ⫾ 0.24
66 (11.8) 71 ⫾ 11 1.93 ⫾ 0.28
218 (39.1) 68 ⫾ 11 1.97 ⫾ 0.26
58 (10.4) 64 ⫾ 10 2.02 ⫾ 0.27
216 (38.7) 70 ⫾ 10 1.92 ⫾ 0.24
342 (61.3) 68 ⫾ 11 1.97 ⫾ 0.26
79 54 54 13 33 54 38 25
77 23 67 20 35 36 32 14
78 24 59 26 50 53 43 26
79 21 48 33 48 52 36 27
75 19 52 35 51 46 35 27
71 12 43 32 49 58 45 17
78 27 61 23 43 48 39 22
75 18 50 34 50 49 37 25
HSMR, hemodynamically significant mitral regurgitation; NHSMR, hemodynamically nonsignificant mitral regurgitation; SD, standard deviation; NYHA, New York Heart Association.
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Journal of Cardiac Failure Vol. 10 No. 4 August 2004 Table 2. Correlation of Echocardiographic Parameters and Severity of Mitral Regurgitation*
Parameter Ejection fraction, % Left ventricular end-diastolic dimension, mm Left ventricular end-systolic dimension, mm Left atrial dimension, mm E/A ratio Deceleration time, ms Right ventricular systolic pressure, mm Hg
Severe (n ⫽ 24)
Moderate-severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-moderate (n ⫽ 66)
Mild (n ⫽ 218)
Trace/no (n ⫽ 58)
r†
P
18 ⫾ 5 72 ⫾ 8
19 ⫾ 7 67 ⫾ 10
21 ⫾ 7 65 ⫾ 12
21 ⫾ 7 67 ⫾ 12
23 ⫾ 9 65 ⫾ 9
24 ⫾ 8 64 ⫾ 11
⫺0.193 0.119
⬍ .001 .027
63 ⫾ 9
60 ⫾ 10
57 ⫾ 10
57 ⫾ 12
56 ⫾ 10
52 ⫾ 11
0.188
.001
55 ⫾ 7 1.99 ⫾ 0.54 145 ⫾ 34 63 ⫾ 16
54 ⫾ 9 2.19 ⫾ 0.76 141 ⫾ 32 60 ⫾ 12
52 ⫾ 8 1.97 ⫾ 1.04 150 ⫾ 34 55 ⫾ 13
50 ⫾ 9 2.31 ⫾ 1.09 161 ⫾ 42 53 ⫾ 15
50 ⫾ 8 1.42 ⫾ 0.89 164 ⫾ 50 47 ⫾ 13
48 ⫾ 8 1.08 ⫾ 0.81 192 ⫾ 57 43 ⫾ 16
0.227 0.428 ⫺0.026 0.376
⬍ ⬍ ⬍ ⬍
.001 .001 .001 .001
E/A, early/late mitral inflow velocity. *Continuous data are presented as mean ⫾ standard deviation. † Spearman correlation coefficient.
Discussion
ventricular assist devices are used, and the nature of our transplant program, which has fairly stringent upper age limitations, related in part to the low numbers of organs available and the relatively long waiting time. The limited availability of these “bailout” procedures may limit enthusiasm for this procedure in our population. Thus the low use reported in the present study must be considered in view of the characteristics of our advanced heart failure population, which may be quite different from those observed elsewhere. It does not imply that surgical therapy of mitral regurgitation may not be of benefit. The relationship of the coronary sinus to the mitral annulus and the success with instrumentation of the coronary sinus for biventricular pacing in advanced CHF have led to efforts to perform mitral annuloplasty with devices placed in the coronary sinus.12 This approach may eliminate functional MR in patients with advanced CHF without a surgical procedure. Because heart failure specialists would be most likely to initiate surgical or device mitral annuloplasty as a therapy for advanced CHF, we sought to determine how many heart failure clinic patients with advanced CHF have significant MR and how often mitral annuloplasty is used. The degree of MR can be overestimated or underestimated by the use of color flow Doppler imaging to assess the central MR jets commonly present in patients with functional MR.17 For this reason, we confined our analysis to patients who were evaluated when quantitative analysis of MR severity was available for most patients and when medical therapy for CHF reflected current practice. We found that severe or moderate-severe MR was present in 16.8% of patients with advanced CHF and moderate or
Among patients with advanced systolic CHF referred to the heart failure clinic, we found that HSMR was common and was frequently associated with severe or moderatesevere tricuspid regurgitation. Quantitative assessment was available for most patients classified as having HSMR. Although the severity of MR was correlated with systolic and diastolic dysfunction, ventricular dilatation, and pulmonary hypertension, it was not an independent predictor of mortality. Few patients were treated with valve repair at our institution during the period of our study. Functional MR in Advanced CHF
Promising results have been reported from centers that use surgical mitral annuloplasty—often combined with tricuspid annuloplasty—as a therapy for advanced CHF. In select patients with advanced CHF and severe functional MR, surgical mortality was low and significant improvement in symptoms, and perhaps survival, was observed.8,10 Few patients evaluated at our heart failure clinic were ultimately treated with surgical mitral annuloplasty. We did not assess how many patients were referred for consideration for such therapy. The low use of surgical annuloplasty in the patients seen in our heart failure clinic is most likely primarily related to the advanced age and comorbidity observed among our patients with severe MR, whose mean age was 70 ⫾ 7 years. The mean age in a large series of patients (n ⫽ 92) treated surgically was 60 ⫾ 6 years.16 The low use may also reflect the nature of our surgical program, in which relatively few
Table 3. Quantitative Assessment of Mitral Regurgitation According to Severity in Advanced Congestive Heart Failure* Characteristic
Severe (n ⫽ 24)
Moderate-Severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-Moderate (n ⫽ 66)
Mild (n ⫽ 218)
r†
P
No. of patients with PISA (%) ERO, cm2 Regurgitant volume, mL
21 (88) 0.49 ⫾ 0.20 66 ⫾ 24
55 (79) 0.30 ⫾ 0.09 43 ⫾ 12
80 (66) 0.22 ⫾ 0.07 33 ⫾ 9
30 (45) 0.17 ⫾ 0.07 27 ⫾ 9
30 (14) 0.12 ⫾ 0.05 18 ⫾ 6
0.743 0.734
⬍ .001 ⬍ .001
PISA, proximal isovelocity surface area; ERO, estimated regurgitant orifice. *Continuous data are presented as mean ⫾ standard deviation. † Spearman correlation coefficient.
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Table 4. Severity of Tricuspid Regurgitation According to Severity of Mitral Regurgitation Severe (n ⫽ 24) Severity of tricuspid regurgitation Severe Moderate-severe
Moderate-Severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-Moderate (n ⫽ 66)
Mild (n ⫽ 218)
Trace/No (n ⫽ 58)
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
7 5
29 21
11 12
16 17
5 13
4 11
4 4
6 6
3 2
1 1
1 0
2 0
worse MR was present in 39%. The severity of MR was confirmed by quantitative analysis in most of these patients. These data are unique because few studies have assessed the prevalence of MR, and they have not assessed it in patients with advanced CHF who are most likely to be considered for mitral valve repair. The frequency of HSMR observed in these patients with advanced CHF greatly exceeded that observed in the Survival and Ventricular Enlargement trial, in which only 0.2% of patients with previous myocardial infarction and systolic dysfunction but without clinical heart failure had severe MR on ventriculogram.4 Similarly, in a preliminary report from the Duke Catheterization Data Base, only 16.7% of patients with moderate or severe CHF (NYHA class II–IV) had moderate or severe MR at ventriculography.18 Another study examined a large
echocardiographic database and reported that 18.9% of patients with systolic dysfunction had severe MR; however, the study did not provide quantitative analysis to confirm the severity of MR, did not exclude subjects with primary valve disease, and did not report data on the presence or severity of CHF.6 The current data suggest that if the benefit of surgical or device therapy for functional MR is confirmed, a substantial number of patients with advanced CHF may be candidates for this type of therapy. The severity of MR correlated with several markers of hemodynamic and structural derangement in patients with advanced CHF. Results of previous studies have suggested that functional MR is more closely related to local rather than global ventricular remodeling;19 however, we found an association between the degree of ventricular dilatation and
Fig. 1. Kaplan-Meier survival curves. (Top left) Survival for all patients. (Top right) Overall survival for patients by severity of mitral regurgitation. (Bottom left) Survival for patients with hemodynamically significant (HSMR) and hemodynamically nonsignificant (NHSMR) mitral regurgitation. (Bottom right) Survival for patients with estimated regurgitant orifice (ERO) ⱖ0.20 cm2 or ERO ⬍0.20 cm2.
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Journal of Cardiac Failure Vol. 10 No. 4 August 2004 Table 5. Mean and Median Survival and 1-, 2-, 3-, and 5-Year Survival Rates Among Patients With Mitral Regurgitation Severity of Mitral Regurgitation
Survival Mean ⫾ SD, d Median, d 1-year, % 2-year, % 3-year, % 5-year, %
Cause
Overall
Severe
Moderate-Severe
Moderate
Mild-Moderate
Mild
Trace/none
Ischemic
Idiopathic
1199 ⫾ 38 1207 77 64 54 37
1126 ⫾ 68 1712 73 62 62 26
1043 ⫾ 98 975 74 57 49 37
1086 ⫾ 79 1012 76 58 48 28
822 ⫾ 60 950 75 60 44 40
1251 ⫾ 60 1344 79 67 57 41
1111 ⫾ 68 1384 88 78 67 42
958 ⫾ 48 729 70 51 40 25
1495 ⫾ 53 2090 87 79 70 54
SD, standard deviation; d, day.
the severity of MR, even in this homogeneous group with severe systolic dysfunction inclusive of patients with and without coronary artery disease. An association between the degree of ventricular dilatation and the severity of MR in patients with systolic dysfunction was also noted in previous studies.4,6,7 Although not performed in the present study, a more sophisticated analysis of ventricular morphologic features may have shown a tighter correlation with local remodeling. The severity of MR also correlated with the E/ A ratio, the deceleration time, and the degree of pulmonary hypertension—all indexes correlated with filling pressures in systolic CHF. These findings are consistent with the correlation noted between the severity of MR and the functional class, even in this population restricted to those with advanced CHF (NYHA class III or IV). Although these findings do not elucidate the degree to which MR affects filling pressures or symptoms in advanced CHF, they do suggest that MR exacerbates symptoms in CHF, a concept supported by other studies7,20 and by the improvement in symptoms reported in patients with advanced CHF treated with mitral annuloplasty.8,10,11 In the present study, patients with HSMR frequently had concomitant tricuspid regurgitation. Indeed, 50% of those with severe MR and 25% of those with HSMR had severe or moderate-severe tricuspid regurgitation. Furthermore, the severity of tricuspid regurgitation correlated more strongly with mortality than did the severity of MR. These data are particularly important in regard to device therapy for MR where the severity of tricuspid regurgitation would not be modified beyond the relief afforded by the reduction in MR.
Prognostic Significance of Functional MR in Advanced Systolic CHF
Patients with advanced systolic CHF have an extremely poor prognosis, and many parameters that reflect outcomes in unselected CHF populations are not predictive for patients with advanced systolic CHF. Indeed, metabolic stress testing was in part developed and validated to address the need for more accurate prognostication for patients with advanced systolic CHF referred for transplantation.21 Thus it is not surprising that our study did not find MR to be an independent predictor of mortality among consecutive patients with advanced systolic CHF evaluated in the heart failure clinic, even though studies of unselected patients with systolic dysfunction3,4,6,7,18 or nonconsecutive series3 have confirmed the prognostic significance of MR. A smaller study of patients with idiopathic dilated cardiomyopathy (NYHA class I–IV) also did not find that MR was an independent predictor of mortality.22 The more consistent use of CHF therapies in patients evaluated in the heart failure clinic may also influence outcomes and obscure the relationship between MR and mortality observed in patients selected from other sources in which CHF therapies may be less consistently applied. Our data do not exclude the likelihood that functional MR contributes to the progression of ventricular dysfunction to CHF and, ultimately, death. However, they do raise the concern that the reduction of MR severity would affect survival in patients with advanced CHF less than it would affect symptoms. Indeed, on the basis of studies of unselected patients with systolic dysfunction, one might speculate that, as with MR resulting from organic mitral valve disease,
Table 6. Multivariate Analysis of Survival Among Patients With Advanced Congestive Heart Failure Overall (n ⫽ 543) Characteristic Age (per year) Sex (M vs. F) Cause (ischemic vs. idiopathic) Ejection fraction (per %) NYHA class (III vs. IV) MR (HSMR vs. NHSMR)
Relative risk (95% confidence interval) 1.02 1.03 1.47 0.98 0.86 0.99
(1.01–1.04) (0.88–1.22) (1.27–1.70) (0.96–0.99) (0.75–1.00) (0.76–1.29)
Ischemic (n ⫽ 390)
Idiopathic (n ⫽ 253)
P
Relative risk (95% confidence interval)
P
Relative risk (95% confidence interval)
P
.002 .713 ⬍ .001 .011 .059 .953
1.01 (0.99–1.03) 0.94 (0.77–1.17) — 0.97 (0.94–0.99) 0.87 (0.74–1.04) 0.88 (0.65–1.20)
.134 .575 — .004 .135 .423
1.04 (1.01–1.06) 1.19 (0.92–1.56) — 0.99 (0.96–1.02) 0.89 (0.67–1.20) 1.25 (0.76–2.03)
⬍ .002 .194 — .746 .415 .373
NYHA, New York Heart Association; MR, mitral regurgitation; HSMR, hemodynamically significant mitral regurgitation; NHSMR, hemodynamically nonsignificant mitral regurgitation.
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earlier treatment of MR (before progression to advanced CHF) may be a more prudent approach.23–27 However, more studies are needed before the use of mitral annuloplasty can be advocated for less severe functional MR or less severe CHF. Limitations of the Study
Our study was retrospective and was restricted to patients with echocardiograms performed at our institution at the time of their evaluation at the heart failure clinic. We did not explore the interaction of factors such as medication and comorbidities on the relationship between MR and survival. We had no information on the cause of death. PISA measurements were not available for most patients with mild MR. Conclusions The CHF population is unique, and introduction of surgical or device-based MR reduction as a therapy for patients with CHF and functional MR must be evaluated in the context of CHF therapy. In the present study, we found that HSMR as assessed by quantitative Doppler echocardiography is common among patients with advanced CHF evaluated in the heart failure clinic. “Stand-alone” mitral valve annuloplasty is performed uncommonly in the CHF patients seen at our institution and may reflect the elderly nature of our patient population. Concomitant tricuspid regurgitation was common and of prognostic importance, a finding that may influence future use of device-based mitral annuloplasty. The strong correlation between MR severity and mortality noted in unselected patients with systolic dysfunction was lacking in patients with advanced CHF. Further studies are needed to determine the role of MR reduction as a treatment strategy to improve survival among patients with advanced CHF.
References 1. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107–12. 2. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. Am Heart J 1997;133:703–12. 3. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759–64. 4. Lamas GA, Mitchell GF, Flaker GC, Smith SC Jr, Gersh BJ, Basta L, et al. Clinical significance of mitral regurgitation after acute myocardial infarction: survival and Ventricular Enlargement Investigators. Circulation 1997;96:827–33. 5. Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991; 122:763–71.
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6. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002; 144:524–9. 7. Junker A, Thayssen P, Nielsen B, Andersen PE. The hemodynamic and prognostic significance of echo-Doppler-proven mitral regurgitation in patients with dilated cardiomyopathy. Cardiology 1993;83:14–20. 8. Bolling SF, Pagani FD, Deeb GM, Bach DS. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381–6. 9. Byrne JG, Aranki SF, Cohn LH. Repair versus replacement of mitral valve for treating severe ischemic mitral regurgitation. Coron Artery Dis 2000;11:31–3. 10. Bolling SF, Smolens IA, Pagani FD. Surgical alternatives for heart failure. J Heart Lung Transplant 2001;20:729–33. 11. Bach DS, Bolling SF. Improvement following correction of secondary mitral regurgitation in end-stage cardiomyopathy with mitral annuloplasty. Am J Cardiol 1996;78:966–9. 12. Osterle SN, Gillinov AM, Chin C-H, Xing Y-Q, Prado AD, Pandian NG. Percutaneous catheter-based mitral valve repair [abstract]. J Am Coll Cardiol 2002;39(Suppl A):432A. 13. Ling LH, Enriquez-Sarano M, Seward JB, Tajik AJ, Schaff HV, Bailey KR, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417–23. 14. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493–6. 15. Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone. J Am Coll Cardiol 1997;30:8–18. 16. Smolens IA, Pagani FD, Bolling SF. Mitral valve repair in heart failure. Eur J Heart Fail 2000;2:365–71. 17. McCully RB, Enriquez-Sarano M, Tajik AJ, Seward JB. Overestimation of severity of ischemic/functional mitral regurgitation by color Doppler jet area. Am J Cardiol 1994;74:790–3. 18. Trichon BH, Felker GM, Shaw LK, Cabell CH, O’Connor CM. Mitral regurgitation is an independent risk factor for mortality in patients with heart failure and left ventricular systolic function [abstract]. J Am Coll Cardiol 2002;39(Suppl A):194A. 19. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;102:1400–6. 20. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29:153–9. 21. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778–86. 22. Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: relation to symptoms and prognosis. Circulation 1994; 90:2772–9. 23. Thomson HL, Enriquez-Sarano M, Tajik AJ. Timing of surgery in patients with chronic, severe mitral regurgitation. Cardiol Rev 2001;9: 137–43. 24. Enriquez-Sarano M. Timing of mitral valve surgery. Heart 2002;87: 79–85. 25. Enriquez-Sarano M, Basmadjian AJ, Rossi A, Bailey KR, Seward JB, Tajik AJ. Progression of mitral regurgitation: a prospective Doppler echocardiographic study. J Am Coll Cardiol 1999;34:1137–44. 26. Enriquez-Sarano M, Schaff HV, Frye RL. Early surgery for mitral regurgitation: the advantages of youth. Circulation 1997;96:4121–3. 27. Enriquez-Sarano M, Schaff HV, Orszulak TA, Bailey KR, Tajik AJ, Frye RL. Congestive heart failure after surgical correction of mitral regurgitation: a long-term study. Circulation 1995;92:2496–503.
Mitral Regurgitation in Patients With Advanced Systolic Heart Failure JEETENDRA B. PATEL, MD,1 DANIEL D. BORGESON, MD,1 MARION E. BARNES,1 CHARANJIT S. RIHAL, MD,1 RICHARD C. DALY, MD,2 AND MARGARET M. REDFIELD, MD1 Rochester, Minnesota
ABSTRACT Background: Mitral regurgitation (MR) may develop in patients with advanced systolic congestive heart failure (CHF) without organic mitral valve disease and contribute to worsening symptoms and survival. Surgical mitral annuloplasty improves symptoms in patients with advanced CHF, and percutaneous approaches to mitral annuloplasty are being developed. Our objective was to define the prevalence, clinical correlates, and prognostic implications of functional MR and the use of mitral annuloplasty in patients with advanced systolic CHF evaluated in a heart failure clinic. Methods and Results: We reviewed clinical, echocardiographic, and survival data from all patients with advanced systolic CHF (New York Heart Association class III or IV; ejection fraction ⱕ35%) resulting from ischemic or idiopathic cardiomyopathy who were evaluated at our heart failure clinic between January 1996 and September 2001. Of 716 patients with advanced CHF, 558 had satisfactory baseline echocardiograms performed at our institution. Among these patients, MR was severe in 24 (4.3%), moderate-severe in 70 (12.5%), moderate in 122 (21.9%), mild-moderate in 66 (11.8%), mild in 218 (39.1%), and absent or present as only a trace in 58 (10.4%). The severity of MR was confirmed by quantitative analysis in 72% of patients with hemodynamically significant MR (more than moderate). The severity of MR correlated with the severity of systolic dysfunction (P ⬍ .001), ventricular dilatation (P ⬍ .03), atrial dilatation (P ⬍ .001), diastolic dysfunction (P ⬍ .001), and pulmonary hypertension (P ⬍ .001). Coexistent severe or moderate-severe tricuspid regurgitation was present in 25% of patients with hemodynamically significant MR. Patients with hemodynamically significant MR had higher mortality (P ⫽ .03) but not when controlling for age, sex, cause, New York Heart Association class, and ejection fraction (P ⫽ .95). Only 3 patients subsequently underwent mitral valve repair. Conclusion: Among patients with advanced CHF, hemodynamically significant MR is common. The severity of MR did not provide independent prognostic information in this group recognized to have uniformly high mortality. Key Words: Congestive heart failure, Prognosis, Tricuspid valve regurgitation.
Congestive heart failure (CHF) is a common, costly, lethal syndrome that affects an estimated 4.7 million Americans, with 550,000 new cases diagnosed annually.1 As many as 25% of these patients has advanced disease (New York Heart Association [NYHA] class III or IV).2 Treatment strategies for advanced CHF are limited.
Mitral regurgitation (MR) may develop in patients with severe systolic dysfunction and left ventricular dilatation without organic mitral valve disease (ie, functional MR). Hemodynamically significant MR (HSMR) may exacerbate the hemodynamic strain on the failing left ventricle, contributing to worsening symptoms and survival. Indeed, in previous studies, MR was associated with increased cardiovascular mortality among unselected patients with prior myocardial infarction3,4 or systolic dysfunction5–7 identified from echocardiographic, catheterization, or clinical trial databases. Surgical mitral annuloplasty improves symptoms in patients with advanced CHF,8–11 and percutaneous approaches to mitral annuloplasty are being developed for treatment of functional MR in CHF.12 The effect of mitral annuloplasty on survival is unclear, but initial data suggest that correction of MR may improve survival for patients with advanced CHF.8–11 However, the number of patients potentially eligible
From the Divisions of 1Cardiovascular Diseases and Internal Medicine and 2Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota. Manuscript received June 23, 2003; revised manuscript received December 15, 2003; revised manuscript accepted December 19, 2003. Reprint requests: Margaret M. Redfield, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Funding by Marriott Foundation, Miami Heart Research Institute, Mayo Foundation, and the National Institutes of Health (T32-HL07111-27). 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2003.12.006
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for surgical or percutaneous annuloplasty is unclear because there are few data on the prevalence of functional MR in patients with advanced CHF. The objective of this study was to define the prevalence, clinical and echocardiographic correlates, and prognostic implications of functional MR in patients with advanced systolic CHF evaluated in the heart failure clinic at our tertiary referral center. Further, we sought to determine the current use of mitral valve repair as therapy for advanced CHF at our institution. Methods Study Population The Mayo Foundation Institutional Review Board approved this study. Mayo Clinic maintains a database of all patients initially evaluated at the Mayo Clinic Heart Failure Clinic since its inception in 1991. The data include demographic characteristics, severity of CHF (NYHA class), cause of ventricular dysfunction, and ejection fraction (EF). We selected patients who had advanced symptoms (NYHA class III or IV) and reduced systolic function (EF ⱕ35%) resulting from ischemic or idiopathic dilated cardiomyopathy. The diagnosis of ischemic or idiopathic cardiomyopathy was made by the heart failure clinician after the initial comprehensive evaluation and review of all pertinent laboratory tests, which typically included perfusion imaging, confirmation of previous history of myocardial infarction, or angiography. This impression was entered in the heart failure database. We excluded patients whose echocardiograms were not performed at Mayo Clinic, patients with inadequate or incomplete echocardiograms, and patients with organic mitral valve disease (mitral stenosis, mitral prolapse, or rheumatic or degenerative MR) that was identified at echocardiography. To increase the percentage of patients in whom the severity of MR was confirmed by quantitative analysis, our study was restricted to patients identified between January 1, 1996, and September 14, 2001, because routine quantitative assessment of MR was incorporated into our echocardiographic laboratory in the first half of the 1990s. Patients who had prior or subsequent mitral valve procedures or cardiac transplantation at Mayo Clinic were identified by reference to the cardiac surgical database and the medical record. Echocardiography Left ventricular end-diastolic, left ventricular end-systolic, and left atrial dimensions were obtained by M-mode echocardiography guided by 2-dimensional imaging. EF was measured by M-mode, 2-dimensional, or semiquantitative visual estimate, and the value for EF was used unaltered from the echocardiographic report as previously reported.3,13 The presence of organic mitral valve disease was assessed by 2-dimensional imaging of the mitral valve, and the existence of several features was sought: mitral valve prolapse, flail mitral valve leaflet, prosthetic mitral valve, and rheumatic or degenerative mitral valve thickening or calcification. Data on the severity of MR were entered unaltered from the echocardiographic report by electronic transfer. Routine assessment of MR in our echocardiographic laboratory incorporates semiquantitative methods (color flow imaging and pulmonary venous flow pulsed wave Doppler integration) and quantitative methods (quantitative Doppler and proximal isovelocity surface area [PISA]). The severity of MR was graded according to the following scale: trace/no, mild, mildmoderate, moderate, moderate-severe, or severe. The severity of
MR was also characterized according to proposed hemodynamic significance and was described as being HSMR (severe, moderatesevere, or moderate) or hemodynamically nonsignificant MR (NHSMR) (mild-moderate, mild, or trace/no), as previously described.3 Although use of the PISA method is recommended for calculating the regurgitant volume and estimated regurgitant orifice (ERO) in the routine assessment of MR in our laboratory, it was not performed or was not possible to perform for all patients. Severity of tricuspid valve regurgitation was assessed by use of color flow imaging and color flow and pulsed-wave Doppler interrogation of the hepatic veins and was graded similarly to severity of MR. Pulmonary artery systolic pressure was estimated by measurement of the tricuspid regurgitation velocity and estimation of the right atrial pressure on the basis of imaging of the inferior vena cava, as previously described.14 Diastolic function was assessed by measurement of the early (E) and late (A) mitral inflow velocities, the E/A ratio, and the E deceleration time as measured by pulsed-wave Doppler.15 Survival Data The dates of death of the patients who died during the followup period were determined using the Social Security Death Index (available at commercial genealogy Web sites [eg, www.ancestry. com]) as of August 31, 2002. Follow-up data were unavailable for 12 patients for whom the Social Security number was not recorded. After the exclusion of 3 patients who underwent mitral valve repair or replacement during the follow-up period, 543 patients were included in survival analysis. For the purpose of the survival analysis, for the 4 patients receiving a cardiac transplant, the date of transplantation was considered to be the date of death. All patients receiving a transplant were classified as United Network for Organ Sharing status I at the time of transplantation. Statistical Analysis Continuous variables were expressed as mean ⫾ standard deviation (SD). Group comparisons between MR grades were performed by analysis of variance (Kruskal-Wallis test). The correlation between MR severity and clinical or echocardiographic variables was assessed by calculation of Spearman rank correlation coefficients. The survival rate free of all causes of death was estimated using the Kaplan-Meier method, and the association with MR severity and other variables was assessed using the log-rank test. The Cox proportional hazards regression model was used to adjust the association of MR or tricuspid regurgitation severity with allcause mortality for age, sex, NYHA class, EF, and cause of ventricular dysfunction. Analyses were performed using GraphPad Prism version 3.0 for Windows (GraphPad Software, San Diego, California) or JMP software (SAS Institute Inc, Cary, North Carolina).
Results Patient Characteristics
During the study period, data for 3357 new patients were entered in the Mayo Clinic Heart Failure Clinic database. Data for 3336 patients included a cause, NYHA class, and EF. A total of 716 patients had NYHA class III or IV CHF and EF ⱕ35% related to ischemic or idiopathic dilated cardiomyopathy. Of these, 608 had an echocardiogram at Mayo Clinic at the time of their heart failure clinic evaluation. Patients
Mitral Regurgitation in Heart Failure
with incomplete or inadequate echocardiograms (n ⫽ 33) or previous mitral valve surgery (n ⫽ 17) were excluded from analysis, leaving 558 patients in the study group. Of these, 3 patients had mitral valve surgery subsequent to the heart failure clinic evaluation and were excluded from the survival analysis, and 4 patients had cardiac transplantation subsequent to the heart failure clinic evaluation. None of the 558 patients selected in this manner were identified as having organic mitral valve disease at echocardiography. Of the patients excluded because they had mitral valve surgery before evaluation at the heart failure clinic, 11 had mitral valve repair or replacement for organic valve disease and 6 had annuloplasty or replacement with no evidence of organic valve disease at the time of bypass grafting (n ⫽ 4) or aneurysmectomy (n ⫽ 2). Of those patients who had mitral valve surgery subsequent to their referral to the heart failure clinic, 2 had annuloplasty at the time of bypass grafting and 1 had annuloplasty at the time of aortic valve replacement for lowoutput, low-gradient aortic stenosis associated with ischemic cardiomyopathy. Table 1 shows the prevalence of the grades of MR in patients with advanced CHF and the characteristics of patients according to the severity and hemodynamic significance of the MR. There was no statistically significant association between MR severity and age, body surface area, sex, or cause (ischemic or idiopathic). The mean NYHA class correlated with the severity of MR (r ⫽ .127, P ⫽ .002). Most patients were male. The frequency of pertinent risk factors in the different groups is also shown. The echocardiographic characteristics of patients with MR are shown in Table 2. The severity of systolic dysfunction, left ventricular and atrial dilatation, diastolic dysfunction, and pulmonary hypertension all correlated with the severity of MR. Quantitative Assessment of MR
Table 3 shows the results of quantitative assessment of the severity of MR with PISA. The frequency with which PISA measurements were performed increased with the severity of the MR. Among patients with HSMR, 72% had
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PISA performed. The average ERO and regurgitant volume correlated strongly with the assigned MR grade. The percentage of patients with severe or moderate-severe tricuspid regurgitation was higher among patients with more severe MR (Table 4). Fifty percent of patients with severe MR and 25% of patients with HSMR had either severe or moderate-severe tricuspid regurgitation. MR and Prognosis in Advanced CHF
Kaplan-Meier survival curves are shown in Fig. 1 for the entire study group and for patients according to the severity of MR by grade, MR designation as HSMR or NHSMR, and ERO. Mean survival time (⫾ SD), median survival, and the 1-, 2-, 3-, and 5-year survival rates are shown in Table 5. Mean survival time was shorter for patients with HSMR (1101 ⫾ 60 days) than for those with NHSMR (1257 ⫾ 48 days) (χ2 ⫽ 4.5; P ⫽ .03). However, in multivariate analysis controlling for age, sex, cause, NYHA functional class, and EF, the severity of MR was not an independent predictor of overall survival (Table 6). When only patients with quantitative assessment of MR (n ⫽ 216) were considered and grouped according to an ERO ⱖ0.20 cm2 or an ERO ⬍0.20 cm2, mean survival time was similar between the 2 groups (1051 ⫾ 71 days and 1136 ⫾ 60 days, respectively) (χ2 ⫽ .47; P ⫽ .49). These findings were similar when patients with ischemic or idiopathic causes were considered separately (Table 6). In multivariate analysis, the cause of ventricular dysfunction was the most important predictor of survival. The mean survival time among patients with advanced CHF resulting from idiopathic cardiomyopathy was 1495 ⫾ 53 days, as compared with 958 ⫾ 48 days among patients with advanced CHF resulting from ischemic cardiomyopathy (P ⬍ .0001). Although the severity of MR was weakly associated with mortality, the severity of tricuspid regurgitation more strongly correlated with outcome in univariate analysis (χ2 ⫽ 18.8; P ⫽ .002). In multivariate analysis controlling for age, sex, NYHA class, cause, and EF, the severity of tricuspid regurgitation tended to be an independent predictor of mortality (χ2 ⫽ 10.5; P ⫽ .06).
Table 1. Patient Characteristics According to Severity and Hemodynamic Significance of Mitral Regurgitation Characteristic No. of patients (%) Mean age ⫾ SD, y Mean body surface area ⫾ SD, m2 Male, % NYHA class IV, % Ischemic cause, % Diabetes, % Hypertension, % Smoking, % Hyperlipidemia, % Atrial fibrillation, %
Severe
Moderate-Severe
Moderate
Mild-Moderate
Mild
Trace/No
HSMR
NHSMR
24 (4.3) 70 ⫾ 7 1.94 ⫾ 0.23
70 (12.5) 68 ⫾ 11 1.89 ⫾ 0.23
122 (21.9) 70 ⫾ 10 1.93 ⫾ 0.24
66 (11.8) 71 ⫾ 11 1.93 ⫾ 0.28
218 (39.1) 68 ⫾ 11 1.97 ⫾ 0.26
58 (10.4) 64 ⫾ 10 2.02 ⫾ 0.27
216 (38.7) 70 ⫾ 10 1.92 ⫾ 0.24
342 (61.3) 68 ⫾ 11 1.97 ⫾ 0.26
79 54 54 13 33 54 38 25
77 23 67 20 35 36 32 14
78 24 59 26 50 53 43 26
79 21 48 33 48 52 36 27
75 19 52 35 51 46 35 27
71 12 43 32 49 58 45 17
78 27 61 23 43 48 39 22
75 18 50 34 50 49 37 25
HSMR, hemodynamically significant mitral regurgitation; NHSMR, hemodynamically nonsignificant mitral regurgitation; SD, standard deviation; NYHA, New York Heart Association.
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Journal of Cardiac Failure Vol. 10 No. 4 August 2004 Table 2. Correlation of Echocardiographic Parameters and Severity of Mitral Regurgitation*
Parameter Ejection fraction, % Left ventricular end-diastolic dimension, mm Left ventricular end-systolic dimension, mm Left atrial dimension, mm E/A ratio Deceleration time, ms Right ventricular systolic pressure, mm Hg
Severe (n ⫽ 24)
Moderate-severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-moderate (n ⫽ 66)
Mild (n ⫽ 218)
Trace/no (n ⫽ 58)
r†
P
18 ⫾ 5 72 ⫾ 8
19 ⫾ 7 67 ⫾ 10
21 ⫾ 7 65 ⫾ 12
21 ⫾ 7 67 ⫾ 12
23 ⫾ 9 65 ⫾ 9
24 ⫾ 8 64 ⫾ 11
⫺0.193 0.119
⬍ .001 .027
63 ⫾ 9
60 ⫾ 10
57 ⫾ 10
57 ⫾ 12
56 ⫾ 10
52 ⫾ 11
0.188
.001
55 ⫾ 7 1.99 ⫾ 0.54 145 ⫾ 34 63 ⫾ 16
54 ⫾ 9 2.19 ⫾ 0.76 141 ⫾ 32 60 ⫾ 12
52 ⫾ 8 1.97 ⫾ 1.04 150 ⫾ 34 55 ⫾ 13
50 ⫾ 9 2.31 ⫾ 1.09 161 ⫾ 42 53 ⫾ 15
50 ⫾ 8 1.42 ⫾ 0.89 164 ⫾ 50 47 ⫾ 13
48 ⫾ 8 1.08 ⫾ 0.81 192 ⫾ 57 43 ⫾ 16
0.227 0.428 ⫺0.026 0.376
⬍ ⬍ ⬍ ⬍
.001 .001 .001 .001
E/A, early/late mitral inflow velocity. *Continuous data are presented as mean ⫾ standard deviation. † Spearman correlation coefficient.
Discussion
ventricular assist devices are used, and the nature of our transplant program, which has fairly stringent upper age limitations, related in part to the low numbers of organs available and the relatively long waiting time. The limited availability of these “bailout” procedures may limit enthusiasm for this procedure in our population. Thus the low use reported in the present study must be considered in view of the characteristics of our advanced heart failure population, which may be quite different from those observed elsewhere. It does not imply that surgical therapy of mitral regurgitation may not be of benefit. The relationship of the coronary sinus to the mitral annulus and the success with instrumentation of the coronary sinus for biventricular pacing in advanced CHF have led to efforts to perform mitral annuloplasty with devices placed in the coronary sinus.12 This approach may eliminate functional MR in patients with advanced CHF without a surgical procedure. Because heart failure specialists would be most likely to initiate surgical or device mitral annuloplasty as a therapy for advanced CHF, we sought to determine how many heart failure clinic patients with advanced CHF have significant MR and how often mitral annuloplasty is used. The degree of MR can be overestimated or underestimated by the use of color flow Doppler imaging to assess the central MR jets commonly present in patients with functional MR.17 For this reason, we confined our analysis to patients who were evaluated when quantitative analysis of MR severity was available for most patients and when medical therapy for CHF reflected current practice. We found that severe or moderate-severe MR was present in 16.8% of patients with advanced CHF and moderate or
Among patients with advanced systolic CHF referred to the heart failure clinic, we found that HSMR was common and was frequently associated with severe or moderatesevere tricuspid regurgitation. Quantitative assessment was available for most patients classified as having HSMR. Although the severity of MR was correlated with systolic and diastolic dysfunction, ventricular dilatation, and pulmonary hypertension, it was not an independent predictor of mortality. Few patients were treated with valve repair at our institution during the period of our study. Functional MR in Advanced CHF
Promising results have been reported from centers that use surgical mitral annuloplasty—often combined with tricuspid annuloplasty—as a therapy for advanced CHF. In select patients with advanced CHF and severe functional MR, surgical mortality was low and significant improvement in symptoms, and perhaps survival, was observed.8,10 Few patients evaluated at our heart failure clinic were ultimately treated with surgical mitral annuloplasty. We did not assess how many patients were referred for consideration for such therapy. The low use of surgical annuloplasty in the patients seen in our heart failure clinic is most likely primarily related to the advanced age and comorbidity observed among our patients with severe MR, whose mean age was 70 ⫾ 7 years. The mean age in a large series of patients (n ⫽ 92) treated surgically was 60 ⫾ 6 years.16 The low use may also reflect the nature of our surgical program, in which relatively few
Table 3. Quantitative Assessment of Mitral Regurgitation According to Severity in Advanced Congestive Heart Failure* Characteristic
Severe (n ⫽ 24)
Moderate-Severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-Moderate (n ⫽ 66)
Mild (n ⫽ 218)
r†
P
No. of patients with PISA (%) ERO, cm2 Regurgitant volume, mL
21 (88) 0.49 ⫾ 0.20 66 ⫾ 24
55 (79) 0.30 ⫾ 0.09 43 ⫾ 12
80 (66) 0.22 ⫾ 0.07 33 ⫾ 9
30 (45) 0.17 ⫾ 0.07 27 ⫾ 9
30 (14) 0.12 ⫾ 0.05 18 ⫾ 6
0.743 0.734
⬍ .001 ⬍ .001
PISA, proximal isovelocity surface area; ERO, estimated regurgitant orifice. *Continuous data are presented as mean ⫾ standard deviation. † Spearman correlation coefficient.
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Table 4. Severity of Tricuspid Regurgitation According to Severity of Mitral Regurgitation Severe (n ⫽ 24) Severity of tricuspid regurgitation Severe Moderate-severe
Moderate-Severe (n ⫽ 70)
Moderate (n ⫽ 122)
Mild-Moderate (n ⫽ 66)
Mild (n ⫽ 218)
Trace/No (n ⫽ 58)
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
7 5
29 21
11 12
16 17
5 13
4 11
4 4
6 6
3 2
1 1
1 0
2 0
worse MR was present in 39%. The severity of MR was confirmed by quantitative analysis in most of these patients. These data are unique because few studies have assessed the prevalence of MR, and they have not assessed it in patients with advanced CHF who are most likely to be considered for mitral valve repair. The frequency of HSMR observed in these patients with advanced CHF greatly exceeded that observed in the Survival and Ventricular Enlargement trial, in which only 0.2% of patients with previous myocardial infarction and systolic dysfunction but without clinical heart failure had severe MR on ventriculogram.4 Similarly, in a preliminary report from the Duke Catheterization Data Base, only 16.7% of patients with moderate or severe CHF (NYHA class II–IV) had moderate or severe MR at ventriculography.18 Another study examined a large
echocardiographic database and reported that 18.9% of patients with systolic dysfunction had severe MR; however, the study did not provide quantitative analysis to confirm the severity of MR, did not exclude subjects with primary valve disease, and did not report data on the presence or severity of CHF.6 The current data suggest that if the benefit of surgical or device therapy for functional MR is confirmed, a substantial number of patients with advanced CHF may be candidates for this type of therapy. The severity of MR correlated with several markers of hemodynamic and structural derangement in patients with advanced CHF. Results of previous studies have suggested that functional MR is more closely related to local rather than global ventricular remodeling;19 however, we found an association between the degree of ventricular dilatation and
Fig. 1. Kaplan-Meier survival curves. (Top left) Survival for all patients. (Top right) Overall survival for patients by severity of mitral regurgitation. (Bottom left) Survival for patients with hemodynamically significant (HSMR) and hemodynamically nonsignificant (NHSMR) mitral regurgitation. (Bottom right) Survival for patients with estimated regurgitant orifice (ERO) ⱖ0.20 cm2 or ERO ⬍0.20 cm2.
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Journal of Cardiac Failure Vol. 10 No. 4 August 2004 Table 5. Mean and Median Survival and 1-, 2-, 3-, and 5-Year Survival Rates Among Patients With Mitral Regurgitation Severity of Mitral Regurgitation
Survival Mean ⫾ SD, d Median, d 1-year, % 2-year, % 3-year, % 5-year, %
Cause
Overall
Severe
Moderate-Severe
Moderate
Mild-Moderate
Mild
Trace/none
Ischemic
Idiopathic
1199 ⫾ 38 1207 77 64 54 37
1126 ⫾ 68 1712 73 62 62 26
1043 ⫾ 98 975 74 57 49 37
1086 ⫾ 79 1012 76 58 48 28
822 ⫾ 60 950 75 60 44 40
1251 ⫾ 60 1344 79 67 57 41
1111 ⫾ 68 1384 88 78 67 42
958 ⫾ 48 729 70 51 40 25
1495 ⫾ 53 2090 87 79 70 54
SD, standard deviation; d, day.
the severity of MR, even in this homogeneous group with severe systolic dysfunction inclusive of patients with and without coronary artery disease. An association between the degree of ventricular dilatation and the severity of MR in patients with systolic dysfunction was also noted in previous studies.4,6,7 Although not performed in the present study, a more sophisticated analysis of ventricular morphologic features may have shown a tighter correlation with local remodeling. The severity of MR also correlated with the E/ A ratio, the deceleration time, and the degree of pulmonary hypertension—all indexes correlated with filling pressures in systolic CHF. These findings are consistent with the correlation noted between the severity of MR and the functional class, even in this population restricted to those with advanced CHF (NYHA class III or IV). Although these findings do not elucidate the degree to which MR affects filling pressures or symptoms in advanced CHF, they do suggest that MR exacerbates symptoms in CHF, a concept supported by other studies7,20 and by the improvement in symptoms reported in patients with advanced CHF treated with mitral annuloplasty.8,10,11 In the present study, patients with HSMR frequently had concomitant tricuspid regurgitation. Indeed, 50% of those with severe MR and 25% of those with HSMR had severe or moderate-severe tricuspid regurgitation. Furthermore, the severity of tricuspid regurgitation correlated more strongly with mortality than did the severity of MR. These data are particularly important in regard to device therapy for MR where the severity of tricuspid regurgitation would not be modified beyond the relief afforded by the reduction in MR.
Prognostic Significance of Functional MR in Advanced Systolic CHF
Patients with advanced systolic CHF have an extremely poor prognosis, and many parameters that reflect outcomes in unselected CHF populations are not predictive for patients with advanced systolic CHF. Indeed, metabolic stress testing was in part developed and validated to address the need for more accurate prognostication for patients with advanced systolic CHF referred for transplantation.21 Thus it is not surprising that our study did not find MR to be an independent predictor of mortality among consecutive patients with advanced systolic CHF evaluated in the heart failure clinic, even though studies of unselected patients with systolic dysfunction3,4,6,7,18 or nonconsecutive series3 have confirmed the prognostic significance of MR. A smaller study of patients with idiopathic dilated cardiomyopathy (NYHA class I–IV) also did not find that MR was an independent predictor of mortality.22 The more consistent use of CHF therapies in patients evaluated in the heart failure clinic may also influence outcomes and obscure the relationship between MR and mortality observed in patients selected from other sources in which CHF therapies may be less consistently applied. Our data do not exclude the likelihood that functional MR contributes to the progression of ventricular dysfunction to CHF and, ultimately, death. However, they do raise the concern that the reduction of MR severity would affect survival in patients with advanced CHF less than it would affect symptoms. Indeed, on the basis of studies of unselected patients with systolic dysfunction, one might speculate that, as with MR resulting from organic mitral valve disease,
Table 6. Multivariate Analysis of Survival Among Patients With Advanced Congestive Heart Failure Overall (n ⫽ 543) Characteristic Age (per year) Sex (M vs. F) Cause (ischemic vs. idiopathic) Ejection fraction (per %) NYHA class (III vs. IV) MR (HSMR vs. NHSMR)
Relative risk (95% confidence interval) 1.02 1.03 1.47 0.98 0.86 0.99
(1.01–1.04) (0.88–1.22) (1.27–1.70) (0.96–0.99) (0.75–1.00) (0.76–1.29)
Ischemic (n ⫽ 390)
Idiopathic (n ⫽ 253)
P
Relative risk (95% confidence interval)
P
Relative risk (95% confidence interval)
P
.002 .713 ⬍ .001 .011 .059 .953
1.01 (0.99–1.03) 0.94 (0.77–1.17) — 0.97 (0.94–0.99) 0.87 (0.74–1.04) 0.88 (0.65–1.20)
.134 .575 — .004 .135 .423
1.04 (1.01–1.06) 1.19 (0.92–1.56) — 0.99 (0.96–1.02) 0.89 (0.67–1.20) 1.25 (0.76–2.03)
⬍ .002 .194 — .746 .415 .373
NYHA, New York Heart Association; MR, mitral regurgitation; HSMR, hemodynamically significant mitral regurgitation; NHSMR, hemodynamically nonsignificant mitral regurgitation.
Mitral Regurgitation in Heart Failure
earlier treatment of MR (before progression to advanced CHF) may be a more prudent approach.23–27 However, more studies are needed before the use of mitral annuloplasty can be advocated for less severe functional MR or less severe CHF. Limitations of the Study
Our study was retrospective and was restricted to patients with echocardiograms performed at our institution at the time of their evaluation at the heart failure clinic. We did not explore the interaction of factors such as medication and comorbidities on the relationship between MR and survival. We had no information on the cause of death. PISA measurements were not available for most patients with mild MR. Conclusions The CHF population is unique, and introduction of surgical or device-based MR reduction as a therapy for patients with CHF and functional MR must be evaluated in the context of CHF therapy. In the present study, we found that HSMR as assessed by quantitative Doppler echocardiography is common among patients with advanced CHF evaluated in the heart failure clinic. “Stand-alone” mitral valve annuloplasty is performed uncommonly in the CHF patients seen at our institution and may reflect the elderly nature of our patient population. Concomitant tricuspid regurgitation was common and of prognostic importance, a finding that may influence future use of device-based mitral annuloplasty. The strong correlation between MR severity and mortality noted in unselected patients with systolic dysfunction was lacking in patients with advanced CHF. Further studies are needed to determine the role of MR reduction as a treatment strategy to improve survival among patients with advanced CHF.
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