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Ann Thorac Surg 2010;89:1524-1531. doi:10.1016/j.athoracsur.2010.01.067
© 2010 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Significance of Left Ventricular Diastolic Function on Outcomes After Surgical Ventricular Restoration

Akira Marui, MD, PhD*, Takeshi Nishina, MD, PhD, Yoshiaki Saji, MD, Kazuhiro Yamazaki, MD, PhD, Takeshi Shimamoto, MD, Tadashi Ikeda, MD, PhD, Ryuzo Sakata, MD, PhD

Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

Accepted for publication January 28, 2010.

Abbreviations and Acronyms A = transmitral late peak filling velocity; CABG = coronary artery bypass grafting; E = transmitral early peak filling velocity; LV = left ventricle; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; NYHA = New York Heart Association; SVR = surgical ventricular restoration

* Address correspondence to Dr Marui, Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara, Sakyo, Kyoto, 606-8507 Japan (Email: marui{at}kuhp.kyoto-u.ac.jp).

Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 
Background: Surgical ventricular restoration (SVR) has been introduced to restore the dilated left ventricular (LV) chamber and improve LV systolic function; however, SVR has also been reported to detrimentally affect LV diastolic properties. We sought to investigate the impact of preoperative LV diastolic function on outcomes after SVR in patients with heart failure.

Methods: Sixty-seven patients (60 ± 14 years) with LV systolic dysfunction (LV ejection fraction, 0.27 ± 0.10) underwent SVR. They were evaluated by echocardiography preoperatively, and early (≤1 month) and late (mean, 3.4 years) after surgery. Patients were divided into three groups according to the preoperative diastolic filling patterns of transmitral flow (impaired relaxation, pseudonormal, and restrictive filling patterns).

Results: Patients in the restrictive group showed far greater cardiovascular mortality than the other two groups (p < 0.0001). The multivariate analysis showed that preoperative restrictive filling pattern was a predominant predictor for adjusted cardiovascular death (p = 0.023; hazard ratio = 3.0). Left ventricular ejection fraction, LV end-diastolic volume, and grade of mitral regurgitation improved in all groups early after surgery; however, these variables in the restrictive group significantly deteriorated late after surgery (from 29 ± 8 to 25 ± 6 for LV ejection fraction; from 183 ± 59 to 226 ± 53 for left ventricular end-diastolic volume; and from 0.7 ± 0.6 to 1.7 ± 0.9 for mitral regurgitation grade; p < 0.05 for all).

Conclusions: In patients with LV systolic dysfunction undergoing SVR, preoperative restrictive LV diastolic filling pattern strongly related to higher mortality with aggravation of LV systolic function, mitral regurgitation grade, or LV remodeling. This might be attributable to deterioration of diastolic function induced by SVR.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Discussion
 References
 
Surgical ventricular restoration (SVR) has been introduced to treat the dilated heart, and it has been well established that SVR improves left ventricular (LV) systolic function by reducing ventricular volumes and increasing the LV ejection fraction (LVEF) [1–6]. However, several experimental studies have reported an adverse effect on diastolic function induced by surgical volume reduction [7–10]. Burkoff and Wechsler [11] also suggested that resection of a portion of the LV wall can detrimentally affect diastolic chamber properties in addition to enhancing certain aspects of systolic chamber properties. However, limited data are available on LV diastolic function in patients with ischemic cardiomyopathy undergoing SVR.

Echocardiography is a common and convenient measure to evaluate cardiac variables including LV diastolic function. In the present study, we used an echocardiographic evaluation of LV diastolic function by three LV diastolic filling patterns, impaired relaxation, pseudonormal, and restrictive filling patterns [12–14]. The purpose of the present study was to investigate the impact of preoperative LV diastolic function on early and late outcomes in patients with ischemic cardiomyopathy undergoing SVR.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 References
 
Patient Population
Between 1999 and 2006, 67 patients underwent SVR for ischemic cardiomyopathy with LV systolic dysfunction (LVEF ≤ 0.40) in our institute. There were 50 men (75%), and a mean age of 60 ± 14 years. The ethics committee approved this study and waived the need for patient consent for the study. Written informed consent for the procedure was obtained from all patients before surgery.

Echocardiography
Transthoracic echocardiography was performed before the operation, 1 to 2 weeks after the operation, and during the follow-up. The LVEF and LV end-diastolic and end-systolic volumes were calculated by the modified biplane Simpson's method. Mitral regurgitation (MR) was classified as none (grade 0), mild (grade1), moderate (2), moderately severe (3), and severe (4). Left ventricular diastolic filling was analyzed from the apical four-chamber view with pulse-wave Doppler sample volume positioned at the leaflet tips of the opened mitral valve. Measurements included transmitral early (E) and late (A) peak filling velocities, their ratio (E/A), E-velocity deceleration time, and isovolumic relaxation time. Three to five cardiac cycles were analyzed. The impaired relaxation filling pattern was defined as an E/A ratio less than 1 with a deceleration time greater than 220 milliseconds and isovolumic relaxation time greater than 100 milliseconds. The pseudonormal filling pattern was defined as an E/A ratio between 1 and 2 with a deceleration time between 150 and 220 milliseconds and isovolumic relaxation time between 60 and 100 milliseconds. The restrictive LV filling pattern was defined as an E/A ratio greater than 2 or an E/A ratio between 1 and 2 with a deceleration time less than 150 milliseconds and isovolumic relaxation time less than 60 milliseconds [12–14]. Patients were assigned to one of the three groups according to their diastolic filling patterns.

Surgical Techniques
Surgical ventricular restorations (Dor and septal anterior ventricular exclusion procedures) were conducted as previously reported [1, 2, 15]. The Dor procedure was performed as follows: a pursestring suture was placed around the circumferential scar tissue at the transition zone and a circular Dacron patch was secured over the opening after a pursestring suture was tied [1, 2]. If there was a significant septal lesion in addition to the anterior-apex lesions, we used a septal anterior ventricular exclusion procedure [15]: after a long left ventriculotomy was made along the left anterior descending artery, an elliptical-shaped Dacron patch was sutured to the transition zone to exclude the akinetic region after broad anteroseptal infarction [15]. The procedures were performed on an arrested heart with cold-blood cardioplegia or on a beating heart partially if possible. Complete coronary revascularization was performed as needed. Undersized mitral annuloplasty or subvalvular procedures such as chordal cutting technique were performed to correct ischemic MR.

Predictive Variables for Cardiovascular Death
The basic characteristics of the patients (sex, age, New York Heart Association [NYHA] functional class, presence of hypertension, and diabetes mellitus), operative data (type of SVR, type of mitral valve surgery, presence of coronary artery bypass grafting [CABG] and number of bypass grafts, cardiopulmonary bypass time, and aortic cross-clamp time), and preoperative echocardiographic data (LVEF, LV end-diastolic volume, LV end-systolic volume, MR grade, diastolic filling patterns) were evaluated as predictive variables of late cardiovascular death. Intensive care protocol after the operation was homogeneous during the whole study period, and medical treatment (eg, diuretics, β-antagonists, calcium-channel blockers, angiotensin-converting enzyme inhibitors) was applied in the same manner during the whole study period.

Statistical Analysis
All continuous variables are expressed as the mean ± standard deviation. Statistical analysis included analysis of variance with the Bonferroni correction for comparisons among the three groups. The repeated measures analysis of variance with Fisher's least significant difference test was used to analyze the data among the three stages in each group. A Cox proportional hazards model was used to identify the predominant predictors of cardiovascular deaths throughout the entire follow-up period by stepwise multivariate analyses. A stepwise selection method was used with a significance level of 0.10 for entering a variable into the model and 0.05 for retaining an explanatory variable from the model. The values of actuarial freedom from cardiovascular death were computed by using the Kaplan-Meier technique, and survival-free curves were compared using the log-rank test. Data analysis was performed with StatView 5.0 for Windows (SAS Institute, Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 References
 
General Features
The baseline characteristics of patients are summarized in Table 1. There were 23 patients with impaired relaxation, and 17 with pseudonormal and 27 with restrictive filling. Operative data are summarized in Table 2. There were no differences in the ratio of procedures such as SVR, mitral valve operations, and CABG among the three groups. Changes in diastolic function after the operation are shown in Table 3. Approximately 70% of patients did not show changes of diastolic pattern after the operation (Table 3A). Diastolic pattern grading worsened early after the operation, but significantly improved late after the operation (p = 0.04; Table 3B). Preoperative NYHA class was higher in the restrictive filling group than those of the other two groups (p = 0.04 each; Table 3C). New York Heart Association grade in the impaired relaxation and pseudonormal groups improved during the study period (p < 0.01 each); however, that in the restrictive group did not change (p = 0.09).


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  		Table 1 Baseline Characteristics
 

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  		Table 2 Operative Data
 

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  		Table 3 Diastolic Function and New York Heart Association Class Change After the Operation
 
Association of Left Ventricular Diastolic Function With Unadjusted Survival
Early after the operation (<1 month), 1 (4%), 2 (12%), and 10 deaths (37%) attributable to cardiovascular events occurred in the impaired relaxation, pseudonormal, and restrictive groups, respectively. Early mortality between 1999 and 2002 was 23% (5 of 21) and that between 2003 and 2006 was 17% (8 of 46). There was no difference in early mortality between the former and latter periods. In addition, early mortalities of each group were not different between the two periods, respectively (eg, 50% versus 43% for the restrictive group). During the mean follow-up of 3.4 years, 4 (17%), 4 (24%), and 6 (22%) patients died in the three groups, respectively. Figure 1A shows the Kaplan-Meier survival curve of all patients. Figure 1B shows the differences in freedom from cardiovascular death among the three groups, which indicates that the freedom from cardiovascular death was far lower in the restrictive group (p < 0.001).


Figure 1
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  		Fig 1. Freedom from cardiovascular death by Kaplan-Meier analysis. (A) All three groups combined. (B) Comparison of the three groups. (Dis. = at discharge; Impaired = impaired relaxation group; m = months; Pseudo = pseudonormal group; Restrictive = restrictive group.)

 
Predominant Predictors for Cardiovascular Death
Univariate analysis by Cox proportional hazard model showed that preoperative NYHA class, severity of MR, LVEF, and the restrictive filling pattern of transmitral flow were significant predictors for cardiovascular death (Table 4). Stepwise multivariate analysis showed that the restrictive filling pattern was the only significant predictor for cardiovascular death (p = 0.023; hazard ratio = 3.0).


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  		Table 4 Preoperative Predictive Variables for Cardiovascular Death (Cox Proportional Hazard Model)
 
Echocardiographic Follow-Up
Perioperative (early) mortality rate was highest in the restrictive group (37%) versus the pseudonormal (12%) and impaired relaxation groups (4%). Late follow-up results of echocardiography were analyzed in 54 survivors (Table 5).


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  		Table 5 Changes in Echocardiographic Data During the Study Period
 
Left ventricular ejection fraction in the restrictive group was lower than that of the other two groups preoperatively and early and late after surgery (p = 0.04, p = 0.01, and p < 0.01, respectively). Left ventricular ejection fraction in the impaired relaxation and the pseudonormal groups significantly improved during the study period (p < 0.01 and p = 0.03, respectively); however, LVEF in the restrictive group did not change (p = 0.44).

Left ventricular end-diastolic volume was not different among the three groups preoperatively and early after surgery (p = 0.76 and p = 0.18, respectively). Left ventricular end-diastolic volume in the restrictive group was highest among the three groups during the follow-up (p < 0.01). Left ventricular end-diastolic volume in the impaired relaxation and the pseudonormal groups reduced during the study period (p = 0.02 and p = 0.03, respectively); however, LV end-diastolic volume in the restrictive group increased during the follow-up and did not change during the study period (p = 0.29).

Preoperative MR grade was highest in the restrictive group (p = 0.02). Mitral regurgitation grade was not different among the three groups early after surgery (p = 0.56). Mitral regurgitation grade in the impaired relaxation and pseudonormal groups improved during the whole study period (p = 0.03 and p < 0.01, respectively); however, MR grade in the restrictive group increased late after surgery and did not change during the whole study period (p = 0.21).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 References
 
Key Findings
In patients with LV systolic dysfunction undergoing SVR, preoperative restrictive LV diastolic filling pattern was strongly related to higher cardiovascular mortality, particularly in the early phase after surgery. Patients with severe diastolic dysfunction showed deterioration of LV systolic function, MR grade, or progression of LV remodeling even though systolic function once improved early after surgery. This study indicates the significance of LV diastolic function after SVR not only early but late after surgery. In the present study, we found that preoperative high NYHA class, low LVEF, and high MR grade were also predominant predictors for cardiovascular death after SVR in patients with ischemic cardiomyopathy, which was compatible with the previous studies [15, 16]. In addition to these factors, we consider preoperative LV diastolic function important in determining surgical strategies for patients with heart failure. It is important to investigate why and which comes first in the factors affected by severe diastolic dysfunction: post-SVR remodeling or recurrence of MR. We speculate that LV remodeling by diastolic dysfunction precedes recurrence of MR because Liu and associates [17] reported that preoperative pseudonormal and restrictive filling patterns were significant prognostic factors for LV remodeling and cardiac events after CABG in patients with coronary artery disease without significant MR.

Diastolic Dysfunction and Surgical Ventricular Restoration
The effect of SVR on ventricular function and the related effect of diastolic dysfunction on outcome after SVR have not been well studied until recently [18]. In 2006, an article by Tulner and colleagues [8] and the accompanying editorial by Burkhoff and Wechsler [11] gave important insights on this topic. The study by Tulner and colleagues [8] was the first in which the end-diastolic pressure–volume relationship was measured in patients before and after SVR. They reported a leftward shift of the end-systolic and end-diastolic pressure–volume relationships with an increased slope of both, suggesting an improvement in systolic function and counteracting changes in diastolic properties as evidenced by an increased stiffness constant. Burkhoff and Wechsler [11] discussed SVR and its effect on LV function within the framework of end-systolic pressure–volume relationship (and end-diastolic pressure–volume relationship). They both indicated probable adverse effects of SVR on LV diastolic function. Menicanti and associates [16] reported that diastolic dysfunction (early-to-late peak filling velocity > 2), when associated with MR and high NYHA functional class, is a risk factor for SVR outcome.

The underlying muscle that is altered during SVR may also affect diastolic function. Buckberg and associates [19] addressed the interaction of the helical components of cardiac form, whereby dysfunction of descending and ascending segments of the heart helix is responsible for septal function. This occurs because both the septum and free wall have the same anatomic descending and ascending segments that cause diastolic dysfunction. In addition, early diastolic filling is directly related to the active process of LV relaxation leading to a "suction" effect, causing blood to flow from the left atrium into the LV across a pressure gradient. This suction effect is thought to be caused by rapid untwisting of the LV apex in early diastole [19]. Impairment of the untwisting action by SVR may influence diastolic function.

Several Factors Influencing Diastolic Function
Although SVR influences diastolic function, several other procedures (factors) may influence diastolic function [20]. First, CABG affects diastolic function independent of SVR. The prognostic value of the LV diastolic filling pattern has been demonstrated in patients with coronary artery disease undergoing CABG [17, 21]. Liu and associates [17] also reported that restrictive LV diastolic filling is the marker of poor prognosis in patients with low LVEF undergoing CABG. Vaskelyte and associates [22] reported the significance of LV diastolic filling pattern in patients with heart failure who are undergoing CABG.

Second, Buckberg and associates [23] provided an important consideration in this problem regarding operative procedure and heart protection. In the present study, operative mortality in the restoration group was 37%, which was higher than the results in the RESTORE registry in advanced disease [21]. A potential problem may be myocardial protection during operation [23]. Although we used conventional cold-blood cardioplegia, improvement of cardioplegia may reduce operative mortality.

Finally, the observation about MR and its worsening postoperatively may be a very important component of the later worsening. The static measurement of MR at rest is now only one of the components that cause MR, as an altered geometry with a wide annulus sets the stage for this complication with exercise. As a result, the measurement of annular size is now used to repair the annulus if it is widened, even if there is no resting MR. Undersized annuloplasty can be performed with low mortality and morbidity, and heart failure class, LVEF, and cardiac output all increase [24].

Diastolic Function and Left Ventricular Shape and Size
The size and shape of the LV after SVR have been reported to influence diastolic function [18, 25]. Although the surgical technique of SVR is not standardized yet and there is the lack of clear indications for SVR, the ability to determine the ideal LV shape and size that facilitates greater improvement of the overall cardiac function is important. Excessive volume reduction probably causes diastolic compliance to shift further to the left on the end-systolic and end-diastolic pressure–volume relationships than EES (end-systolic elastance), thereby producing diastolic heart failure [18]. Regarding LV shape, a new variable named the conicity index, which is calculated as the apical to short-axis ratio, may be more accurate in detecting regional shape abnormalities than the conventional sphericity index [25]. A conicity index greater than 1 can reflect a relatively more compliant tissue, and its resection or exclusion does not affect diastolic function [25]. At the present time, however, there is no objective evidence to support the selection of a particular postoperative LV size [18, 26].

Study Limitations
There are several limitations to the present study. First, this is a retrospective study with a small number of patients with different surgical techniques including SVR. Second, preoperative MR grades in the pseudonormal and the restrictive group were significantly higher than that of the impaired relaxation group, which might influence the results of the study, although multivariate analyses indicated that preoperative MR grade was not a significant predictor. Third, we used conventional mitral inflow indices for the evaluation of LV diastolic filling by pulse-wave Doppler echocardiography. Pulse-wave Doppler echocardiography is influenced by LV loading conditions, and tissue Doppler imaging can better identify diastolic function than pulse-wave Doppler imaging. However, tissue Doppler data were not available in the present study. Fourth, magnetic resonance imaging can provide morphologic, functional, and histologic (myocardial viability) data better than transthoracic echocardiography. However, magnetic resonance imaging was not available from all patients. Finally, transcatheter evaluations such as pressure-volume analysis, pulmonary artery pressure measurement, and left ventriculography may be favorable to evaluate preoperative systolic and diastolic function more accurately.

Conclusions
Preoperative severe diastolic dysfunction may have a significant impact on outcomes after SVR with heart failure. Further study is warranted.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
References
 
DR Y. JOSEPH WOO (Philadelphia, PA): Are you making patients with severe diastolic dysfunction ventricles just too small with this operation?

DR MARUI: No. Too small?

DR WOO: Relative to their diastolic function.

DR MARUI: Not too small, because diastolic dysfunction after surgery is very important to determine the prognosis of the patient. So we did not reduce too much the volume. It is a very important point.

DR ROBERT A. DION (Genk, Belgium): It is a very interesting paper, which is confirming another paper from Marisa Di Donato on this subject. Of course, it is important to recognize that a diastolic restrictive pattern before the operation is a contraindication. What was for me a surprise is that there is a marked difference in mortality between the pseudonormalization and the impaired diastolic pattern groups, 0 versus up to 12%, while the pressure–volume loops do not really differ in these groups. How do you then explain the difference in mortality?

DR MARUI: I want to confirm your question, Doctor. Could you repeat your question again? Sorry.

DR EDWARD D. VERRIER (Seattle, WA): I don't think we should do that at this point because the question is simply too complex to address in this setting.

But I am very pleased that Dr Buckberg stepped up because Gerry has probably studied these issues more than any of us. We have always made so much of the decision-making related to SVR (surgical ventricular restoration) based on anatomic considerations (anterior wall dyskinesia). We have known that very restrictive patterns of diastolic dysfunction were probably not good. Should we be changing the way we think about this, Gerry, based on the data we have got today?

DR GERALD D. BUCKBERG (Los Angeles, CA): This is an important discussion of diastolic dysfunction after surgical ventricular restoration. The restrictive pattern suggests a lot more of the ventricle is abnormal than is normal, in comparison to how echo[cardiography] reports the other two types of dysfunction. You did not reduce volume too much, as stated in response to the question asked by Dr Woo. Therefore, the remaining question is why the ventricle didn't relax well? From my perspective, it is important to also look at the pre- and postoperative function of the septum. During normal diastolic function, the ventricle suctions venous return by an untwisting action. Consequently, abnormal diastolic function occurs if a stretched ventricle doesn't untwist adequately.

The septum is involved with the same muscle mass, because it the architectural construction that involves the descending and ascending segments of the helical heart, which creates this motion. Consequently, if the septum is not working properly, there should also be associated diastolic dysfunction, as it is involved with the same muscle mass that forms the free left ventricular wall.

My question is, did you look at the septum pre- and postoperatively? If the septum was normal postoperatively, I would suspect some of even the restrictive patterns would have improved. Conversely, if the septum was not working properly, that would also translate into the lateral wall not working properly.

Dysfunction of these segments may be closely related to protection, so that if the protection is inadequate, the area that gets damaged is the subendocardium, and that subendocardium muscle mass involves both the septum and the free wall.

To respond to these questions, could you advise us if the ventricle showed untwisting, and could you advise us about septum function pre- and postoperatively?

DR MARUI: Thank you very much for your question. The viability of the septum is very important to design the procedure, and we evaluated the septum viability by magnetic resonance imaging or radiological evaluation, and we determined surgical strategy before operation, and during the operation we directly examined the septum and decided to perform the SAVE (septal anterior ventricular exclusion) procedure and exclude the septum or not exclude the septum during the operation. However, that determination does not completely contribute to the good results. So it is a very difficult point.

DR ADRIAN JEREMY LEVINE (Stoke-on-Trent, UK): I noticed your mean number of grafts was only 1.7. Did you notice that the restrictive pattern was more associated with a smaller number of grafts that you did in any way and was there any group of patients who you did more grafts on who had a restrictive pattern but had any change in diastolic function afterward?

DR MARUI: There might be good patients who are included in the impaired relaxation group. The multivariate analysis also shows mitral regurgitation grade is a significant factor for cardiovascular death. So a prospective study is more important I think.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 References
 

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