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Ann Thorac Surg 2005;80:170-178
© 2005 The Society of Thoracic Surgeons
a Department of Radiology, Section of Cardiovascular Imaging, Cleveland Clinic Foundation, Cleveland, Ohio
b Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
c Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
d Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio
Accepted for publication January 10, 2005.
* Address reprint requests to Dr White, Center for Integrated Non-Invasive Cardiovascular Imaging, Desk HB6, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH44195 (Email: whiter{at}ccisd1.ccf.org).
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Abstract |
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METHODS: Sixty patients with varying degrees of MR (none, mild, moderate, and severe) determined by echocardiography and referred for MRI assessment of ischemic heart disease were included. Left ventricular geometric, functional, and scar measurements in addition to mitral valve geometric measurements were evaluated.
RESULTS: Clinical characteristics found to be significant predictors of degree of MR included severity of coronary artery disease (p < 0.05), completeness of myocardial perfusion (p < 0.005), and average systolic blood pressure (p < 0.05). Mitral systolic tenting area (p < 0.0001) in a statistical model with scarring of the anterior-lateral region (p < 0.05) proved to be the most powerful predictor of MR severity (r2 = 0.31). Mitral annular dilatation in the anterior-posterior direction (p < 0.0001) and diminished LV systolic function (p < 0.005) were important determinants of mitral systolic tenting area (r2 = 0.57).
CONCLUSIONS: Mitral tenting in combination with regional left ventricular myocardial scarring are important mechanisms to the development of ischemic MR. Surgical annuloplasty addresses mitral tenting, but has little impact on the effect of regional scarring. Moderate-to-severe ischemic MR develops in patients with regional scarring of the anterior-lateral and inferior-posterior regions, and new surgical developments should take this into account.
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Introduction |
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The exact mechanical alterations leading to the development of ischemic MR are not well defined. In experimental studies, ischemic MR was attributed to global changes in the LV geometry [3, 4]. More recently, in vitro [5] and animal studies [6–8] have suggested that the pathogenesis is more complex, related to alterations in spatial relationships between the LV and mitral valve apparatus. In human studies, LV sphericalization [9], mitral annulus enlargement, increased mitral tenting area, and loss of systolic mitral annular contraction [10] have been proposed as possible mechanisms. However, limitations with imaging and analysis of MR degree, mitral deformation, and global and local LV remodeling have limited these studies.
Given the diversity of potential mechanisms contributing to the development of ischemic MR, current surgical therapy consisting of mitral annuloplasty with an undersized annular ring does not always provide predictable and durable repair. As a result, newer techniques are under development based on observations from experimental animal models of ischemic MR. Insight into the mechanisms causing ischemic MR is key to further advancement of treatment strategies.
Magnetic resonance imaging (MRI) provides high quality images for the assessment of LV and mitral valve geometric and functional changes. With MRI, quantitative measurements of LV volumes and function do not rely on geometric assumptions and are superior to traditional two-dimensional echocardiography measurements [11]. Additionally, with the advent of delayed-enhancement imaging, the degree of regional and global myocardial scarring can be uniquely analyzed [12]. Therefore, we undertook this retrospective quantitative MRI study of patients with IHD and LV dysfunction, with the hypothesis that the degree of ischemic MR is influenced by regional and global myocardial scarring and its resultant effects on LV geometry and function, as opposed to local changes in the mitral valve apparatus.
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Material and Methods |
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Patient Population
There were 243 patients who underwent a cardiac MRI for functional and anatomic evaluation of the LV and tissue characterization of its myocardium between January 2001 and December 2002. In the subgroup of 180 patients with evidence of IHD and LV systolic dysfunction, defined as LV ejection fraction of 40% or less, there were 128 patients who also had a transthoracic echocardiography performed within 1 week of the cardiac MRI study. Within this group with both cardiac MRI and transthoracic echocardiography performed, we stratified patients by MR severity as determined by echocardiography. Patients with structural abnormalities of the mitral valve apparatus (eg, myxomatous) or other valves (eg, calcific aortic stenosis) were excluded. To achieve a balanced test set, we included the first 15 consecutive qualifying patients per group for a total of 60 patients (Fig 1).
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Echocardiography
Echocardiographic technique
Two-dimensional echocardiography examinations were performed using commercially available equipment and standard techniques in accordance with the guidelines of the American Society of Echocardiography (ASE) [13]. Examinations consisted of multiple tomographic planes including long-axis and short-axis views with color Doppler and continuous wave Doppler for detection and assessment of myocardial function and valvular disease. Degree of MR was assessed semiquantitatively by jet area on color Doppler and quantitatively by calculation of effective regurgitant orifice (ERO) area based on the proximal isovolumic contour method [14].
Severity of mitral regurgitation by echocardiography
Overall severity of MR was graded on echocardiography by qualitative (jet area/left atrial area ratio) and quantitative (ERO) assessments into four grades: none = jet area 0%, ERO 0 mm2; mild = jet area less than 20%, ERO 1 to 10 mm2; moderate = jet area 20% to 40%, ERO 10 to 50 mm2; and severe = jet area greater than 40%, ERO greater than 50mm2.
Magnetic Resonance Imaging
MRI technique
Cardiac MRI was performed on a 1.5-Tesla scanner (Symphony or Sonata; Siemens Medical Systems, Erlangen, Germany) using a phased-array torso coil and standard electrocardiographic referencing techniques [15]. Scout imaging using an ultrafast "snapshot" half-Fourier single-shot, turbo spin-echo sequence [15] permitted rapid identification of the cardiac axes for diagnostic imaging. Dynamic (ie, cine) "bright-blood" image-loops were acquired using a segmented-k-space gradient-echo sequence with view-sharing for a temporal resolution of 30 to 50 msec [15]. For evaluation of myocardial scar, nonstress gadolinium delayed-enhancement MRI images were acquired. Delayed-enhancement MRI was based on the previously described Turbo-FLASH with inversion recovery imaging at 20 to 30 minutes after intravenous injection of Gadolinium-DTPA (0.2 mmol/kg). Imaging was performed with or without breath-holding, based on the patient’s heart rate and ability to suspend respiration.
Images were acquired in standard two-chamber, three-chamber, and four-chamber long-axis views, as well as short-axis views at basal, middle, and apical thirds of the LV. For positioning, the midpapillary muscle level (ie, middle third) was used for reference, with the basal image derived from midway between it (approximately 2 cm above) and the mitral annulus and the apical image derived from midway between it (approximately 2 cm below) and the LV apex. Additionally, a short-axis series (base to apex) of cine MRI loops was acquired for volumetric analysis of the LV.
Left ventricular global geometric measurements
Left ventricular volumetric analysis was performed on the cine MRI LV short-axis series using a standard approach [15]. This was accomplished by manual outlining of the endocardial borders at end-diastole and end-systole at all levels with derivation of end-diastolic volume, end-systolic volume, and ejection fraction using commercially available software (Argus Platform; Siemens Medical Systems, Erlangen, Germany). Volumes were indexed to body surface area. Additionally, the sphericity index (ratio of LV length to width) was also measured.
Left ventricular regional functional measurements
The LV was divided according to the ASE 16-segment model [13]. Segmental wall thickening was assessed qualitatively and graded as a wall motion score for each segment as: 1 = normal, 2 = hypokinetic, and 3 = akinetic/dyskinetic. Total function was assessed as the average wall motion score over the entire ventricle. Additionally, segments adjacent to each papillary muscle were grouped together to form the anterior-lateral region and inferior-posterior region, and function of these regions was taken as the average wall motion score from the basal and middle segments forming these regions.
Left ventricular regional myocardial scar measurements
The extent of myocardial hyperenhancement per LV segment, reflecting scar, was graded using a previously described six-level system as follows: 0%, 1% to 24%, 25% to 49%, 50% to 74%, 75% to 99%, and 100% segmental scar [16]. Total scarring was assessed as the average of the scar grade over the entire LV. Additionally, scarring in the vicinity of the papillary muscles (anterior-lateral and inferior-posterior) was assessed as the average scar grade from the basal and middle segments forming these regions.
Mitral valve geometric measurements
Mitral annular diameter was measured on cine MRI in two-chamber, three-chamber, and four-chamber views (Fig 2) and averaged at end-systole to calculate mean annular diameter. Systolic leaflet deformation, defined as valvular tenting area, was measured as area enclosed between the annular plane and mitral leaflets on the three-chamber view at early and late systole. In addition, apical displacement of the mitral coaptation point (coaptation height) was measured as the distance between the leaflet coaptation point and mitral annulus plane at early systole and late systole (Fig 1).
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2 tests. Associations between each independent variable and grade of MR severity were assessed using Spearman correlation coefficients. To maintain an overall Type I error of 0.05, a simple Bonferroni correction was applied, and a p values less than 0.005 were required in order to declare statistical significance. Predictors that displayed significant (p < 0.005) or marginally significant (0.005 < p < 0.10) relationships with degree of MR in univariate analyses were included in multivariate analysis of variance (ANOVA) models of MR severity. For simplification, regional (as opposed to segmental) variables of function and scarring were used in the statistical analyses. Variables studied in multivariate models of MR severity included the following: LV ejection fraction, LV end-diastolic volume index, sphericity index, average wall motion score in anterior-lateral region, average wall motion score in inferior-posterior region, average scar grade in anterior-lateral region, average scar grade in inferior-posterior region, mitral annulus diameter in anterior-posterior dimension, mitral leaflet coaptation displacement, and early systolic mitral tenting area. |
Results |
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Determinants of Degree of MR
Multivariate ANOVA modeling of MR severity pointed to mitral systolic tenting area as the single most powerful predictor among those studied (p < 0.0001). Anterior-lateral scarring also predicted more severe MR (p < 0.05; Table 3). Global LV parameters including LV ejection fraction, volumes, and sphericity index, and regional parameters of LV function and scar did not affect the determinants of MR severity. Scarring of the inferior-posterior region, when compared directly against scarring of the anterior-lateral region as competing predictors, was found to affect a dimension of MR severity not accounted for by anterior-lateral scarring (p < 0.05).
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Study Findings
Key findings of this study, which employed quantitative MRI to assess the multiple different contributions to ischemic MR as graded by echocardiography, were as follows: (1) even in the setting of LV systolic dysfunction (ejection fraction 
40%), improved function and overall smaller LV volumes are found with no MR compared with any degree of MR; (2) increasing severity of MR correlates with a more spherical LV; (3) LV function in the inferior-posterior, but not anterior-lateral, region shows greater impairment with increasing severity of MR; (4) increased regional and global LV myocardial scarring is seen with increasing severity of MR, and each region (anterior-lateral and inferior-posterior) has an independent impact; (5) mitral annulus diameter is significantly larger with progressive increases in MR severity, but only in the anterior-posterior dimension; and (6) mitral systolic tenting area is the most powerful predictor of MR severity in multivariate analyses.
Current Therapy
Current therapy for patients with IHD and MR remains controversial. In the absence of jeopardized myocardium, medical treatment of MR has mainly been with the use of vasodilators. In the presence of jeopardized myocardium, surgical treatment of ischemic MR generally combines coronary revascularization with correction of MR by valve repair or replacement.
Valve repair for ischemic MR generally consists of reducing annular size using a significantly undersized annuloplasty ring. As such, repair is generally not a physiological correction because, although restoring leaflet coaptation via annular reduction, it does not address the other potential mechanisms leading to leaflet tethering. Additionally, LV remodeling often continues to progress and can lead to MR recurrence despite good initial results [18]. Therefore, new surgical techniques that attempt to address the primary mechanism of ischemic MR are under development using experimental animal models [19–22]. Ischemic MR in these animal models relies on the creation of inferior-posterior infarcts by ligation of obtuse marginal branches of the left circumflex artery.
Mechanisms of Ischemic MR
In the current study, we evaluated the impact of LV myocardial scarring and resultant geometric and functional changes versus changes in mitral valve apparatus geometry on the development of ischemic MR in patients with LV dysfunction. Mitral systolic tenting area was the most powerful predictor of MR severity and significant mitral annular dilatation in the anterior-posterior direction, coaptation height, and diminished LV systolic function were found to be its major determinants. Mitral valve systolic tenting is characterized by insufficient systolic leaflet body displacement toward the annulus, with coaptation limited to the leaflet tips [23]. Interestingly, LV sphericalization, which has been shown in prior studies to be important to development of ischemic MR [3, 4, 9], showed significant impact on univariate, but not multivariate analyses.
Degree of myocardial scarring in the anterior-lateral region was also important to the development of ischemic MR, independent of mitral systolic tenting area. Further analyses, focusing on the interaction of regional scarring, showed that degree of scarring in the inferior-posterior region, independent of anterior-lateral scarring, was important to ischemic MR severity.
Relation to Prior Studies
Our results differ from other studies that have shown higher incidences of ischemic MR in patients with inferior compared with anterior myocardial infarction [24–26]. However, diagnosis of regional scarring in these studies was indirect, based on regional dysfunction which may represent myocardial hibernation as opposed to true myocardial scar. In the present study, regional myocardial scarring was directly detected as hyper-enhancement on delayed-enhancement MRI independent of regional function. Additionally, unlike earlier studies, regions were localized with regard to papillary muscles (anterior-lateral and posteromedial). Nevertheless, our findings are similar to prior studies showing impairment of function in the inferior-posterior, but not the anterior-lateral region, was associated with increasing severity of MR. However, degree of regional scarring as opposed to regional function proved to be a more important determinant of MR severity in multivariate analysis.
Clinical Implications
Current surgical therapy for ischemic MR with the use of an undersized annuloplasty ring has beneficial effects on reduction in the mitral systolic tenting area. However, clinical observations suggest that this repair technique has limited durability in selected patients [27].
Surgical techniques under development for improving treatment of ischemic MR have focused on MR resulting from infarction or ischemia in the inferior-posterior region, with resultant dysfunction and displacement of the posteromedial papillary muscle. Since in our study, moderate-to-severe MR was associated with regional myocardial scarring in the anterior-lateral or inferior-posterior regions, future surgical therapies will need to address ischemic MR in association with inferior-posterior or anterior-lateral regional scarring, or both, because clinically, patients may present with either type. Based on the findings in our study, we would expect that surgical techniques that focus on the impact of LV remodeling resulting from LV myocardial scarring affecting the segments adjacent to the papillary muscles, such as papillary muscle relocation, papillary muscle sling, and infarct restraint procedures, would have impact on improving the degree and recurrence of MR.
Study Limitations
An underlying limitation of this study relates to referral bias of patients with LV dysfunction and scarring in the left anterior descending distribution due to this institution’s interest in surgical ventricular restoration for postinfarction aneurysm. Hence, the increased frequency of ischemic MR due to anterior-lateral scarring may be reflective of referral bias and not necessarily characteristic of the general population with IHD. Additionally, because image analysis was performed retrospectively, incomplete imaging of the papillary muscles limited detailed analysis of papillary muscle function, scarring, and geometry. Finally, technical difficulties with flow measurements using the velocity phase mapping technique limited the quantification of mitral regurgitant fraction by MRI for some patients (n = 19). Consequently, the combination of two echocardiography Doppler methods (jet area and ERO), which have been validated [3, 4], were used for assessment of MR severity.
Conclusion
Quantitative MRI with delayed-enhancement imaging for assessment of LV function, geometry and myocardial scarring is important to (1) add to our understanding of the diverse mechanisms involved in the development of ischemic MR; (2) aid in the design and implementation of newer surgical and nonsurgical approaches to the treatment of patients with ischemic MR; (3) identify patients with other potential mechanisms of ischemic MR, namely, primary involvement of the anterolateral as opposed to posteromedial papillary muscle and adjacent ventricular segments; and (4) identify patients with severe LV geometrical distortion who will likely require more than a simple annuloplasty ring for treatment of the MR. Mitral tenting area in combination with regional LV myocardial scarring localized to either the inferior-posterior or anterior-lateral segments contribute to the development of ischemic MR, and new surgical and nonsurgical developments will need to address the effects of LV remodeling in the vicinity of both papillary muscles for the treatment of patients with ischemic MR.
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