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Eur J Cardiothorac Surg 2004;26:1174-1179
© 2004 Elsevier Science NL

Residual fibrosis affects a long-term result of left ventricular volume reduction surgery for dilated cardiomyopathy in a rat experimental study

Taiko Horiia,b, Keiichi Tambaraa, Kazunobu Nishimuraa, Hisayoshi Sumab, Masashi Komedaa,*

a Department of Cardiovascular Surgery, Graduate school of Medicine, Kyoto University, Kyoto, Japan
b Hayama Heart Center, Hayama, Japan

Received 18 November 2003; received in revised form 11 June 2004; accepted 16 June 2004.

* Corresponding author. Tel.: +81 75 751 3781; fax: +81 75 751 3098. (E-mail: masakom{at}kuhp.kyoto-u.ac.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Result
 4. Discussion
 5. Study limitations
 Appendix A. Conference...
 References
 
Objectives: The aim of this study is to evaluate the relationship between left ventricular (LV) wall property and the results of LV volume reduction surgery (LVR) to treat dilated cardiomyopathy (DCM) in an experimental model. Methods: DCM was introduced in 18 Lewis rats by autoimmunization with cardiac myosin. Among them, 12 rats underwent LVR and the rest were served as controls. They were subjected to echocardiography and cardiac catheterization for dimensional and functional measurements. The animals were sacrificed 4 weeks after surgery, and the fraction of myocardial fibrosis was calculated in 4 divided parts of the LV wall. Results: Percent fibrosis varied widely from 4.7 to 45.2%. LV volume reduction surgery improved cardiac function immediately after surgery in all rats (Emax, 0.28±0.14 to 0.48±0.18mmHg/µl; LV end-diastolic pressure, 21.0±6.1 to 13.3±5.1mmHg, P<0.05, respectively). Four weeks later, 6 hearts remained in good shape with smaller LV end-diastolic dimension (Dd) than baseline values (LV Dd, 9.7±0.6mm; fractional area change (FAC), 40.3±8.4%) and the other 6 had more redilation in diameter and more deterioration in function than baseline values (LV Dd, 10.9±0.6mm; FAC, 25.8±6.9%; P<0.05, respectively). Percent fibrosis in the septum differed 11.1±3.4 vs. 27.8±2.8% between the two groups (P<0.01). There was a significant correlation between the ratio of LV redilatation after surgery and percent fibrosis in the septum (r=0.951, P<0.01). Conclusions: Although the initial benefit of LVR was confirmed, the long-term result was affected by the amount of residual fibrosis. This information suggests that surgical site selection is important to achieve a good result of LV restoration surgery for DCM.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Result
 4. Discussion
 5. Study limitations
 Appendix A. Conference...
 References
 
Initial enthusiasm of partial left ventriculectomy (PLV), so called Batista operation, to treat dilated cardiomyopathy (DCM) has quickly diminished partially due to an unpredictable mid-term result [1,2]

PLV works very well in some patients, but not so well or even worse in others. The reason why the effect of PLV is inconsistent remains unclear so far.

In our clinical practice, we noticed that the left ventricle of DCM was not always homogeneously affected as pointed out previously [3,4]. Some patients have inhomogeneous left ventricular (LV) wall property, and others have diffusely and homogeneously damaged LV wall [5,6].

The hypothesis is that the surgical benefit does not last long if fibrosis was prominent in the retained myocardium after PLV. The main purpose of PLV is to reduce the diameter and the volume of the left ventricle, and therefore we perform LV volume reduction surgery (LVR) as an alternative to PLV in this study. We have focused attention to the LV wall property as assessed by the amount of myocardial fibrosis and evaluated the relationship between the residual fibrosis of the retained myocardium and the surgical result of LV volume reduction surgery in a rat DCM model.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Result
 4. Discussion
 5. Study limitations
 Appendix A. Conference...
 References
 
2.1. Animal information
Young male Lewis rats were used in this study.

All animals received humane care in compliance with Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute Council and published by the National Academy Press.

2.2. DCM model
Six weeks old Lewis rats were autoimmunized with purified cardiac myosin and later on developed DCM as reported elsewhere [7,8]. Animals have suffered from sort of acute myocarditis for 4–5 weeks and such inflammatory reaction almost disappeared within 8 weeks after autoimmunization [9].

Ten weeks after autoimmunization all animals were evaluated by means of echocardiography. Rats with dilated LV and severely depressed LV function confirmed by echocardiography were provided for this study. After all, 18 rats completed the study, among which 12 rats underwent surgical intervention and the rest were served as controls.

2.3. Echocardiographic study
Rats were anesthetized with ether and LV function was assessed by means of echocardiography with a 12MHz phased-array transducer (SONOS 5500, Philips Medical Systems, Bothell, WA, USA) [10–12]. The following parameters were measured from B- and M-mode tracing: LV end-diastolic dimension (LV Dd, mm), LV end-systolic dimension (LV Ds, mm), fractional shortening (FS, %), and fractional area change (FAC, %). All parameters were measured by the American Society for Echocardiography leading-edge method from at least three consecutive cardiac cycles.

Echocardiography was performed before and immediately after surgery, following 2 and 4 weeks after surgery serially.

2.4. LV volume reduction surgery
Animals were orally intubated with ethyl ether gas and anesthesia was maintained with 1% isoflurane under control ventilation during operation. LV volume reduction surgery (LVR) was carried out by placation of the posterolateral wall. LV was gently pulled out from the pericardial cavity via left thoracotomy and the posterolateral wall of the left ventricle was plicated with several horizontal mattress sutures of 4-0 prolene without any kind of cardiac support. Surgical technique performed in this study was similar with the technique adapted to a large animal model, apex-preserving LVR [13]. Before and after surgery, echocardiography and cardiac catheterization were performed simultaneously and the efficacy of the surgical technique was evaluated.

2.5. Cardiac catheterization
A 2 French micromanometer-tipped catheter (Millar Instruments Inc, Houston, TX) was introduced from the right carotid artery to measure LV pressure and a 3 French occlusion balloon catheter was introduced from the right femoral vein to occlude the inferior vena cava. At the stable state, LV pressure and its first time derivative (dp/dt) were continuously monitored through the arterial catheter by using a multiple recording system during temporary caval occlusion. Simultaneously LV dimension was measured by echocardiography. The maximum time-varying elastance (LV Emax, mmHg/µl) and the time constant of isovolumic relaxation (Tau {tau}, ms) was calculated as an index of global systolic and diastolic function, respectively [10–12].

2.6. Histological study
At 4 weeks after surgery, final echocardiography was performed and all rats were sacrificed. Hearts were removed and transected at the base of the papillary muscles. The transverse sections were fixed with 10% formalin and stained with hematoxylin eosin and Masson's trichrome staining. In the same manner six DCM rats without LVR were served as control group.

The heart sections were divided into four parts: anterior, septal, posterior, and lateral part. Masson's trichrome stained sections were subjected to quantitative evaluation of the severity of interstitial fibrosis (percent fibrosis) using the point counting method.

2.7. Statistical analysis
Data were expressed as means±SD. Statistical analysis was performed by using StatView (SAS Institute Inc, Cary, NC). Differences between two groups were assessed by the non-parametric test, Wilcoxon test and Mann–Whitney U-test. Correlation trends were assessed by Spearman rank correlation coefficient r. Values of P less than 0.05 were considered statistically significant.


   3. Result
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Result
4. Discussion
 5. Study limitations
 Appendix A. Conference...
 References
 
3.1. Echocardiography at baseline
Sixty-eight rats out of 100 rats which were autoimmunized with cardiac myosin survived until echocardiographic study at 8 weeks after initial manipulation. Fifty-two rats were diagnosed as DCM by echocardiography. The reasons of exclusion were as follows: LV cavity was not enough enlarged, LV wall motion was too much depressed (i.e. almost dying), or right ventricle was also severely enlarged or depressed.

Table 1 summarized echocardiographic data at baseline. LV Dd and LV Ds of DCM rats became bigger than those of health Lewis rats of the same age (normal control). FS and FAC of DCM rats were lower than those of normal control.


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  		Table 1. Echocardiographic data in control and DCM group
 
DCM rats had significantly larger hearts and poorer LV function than normal control group.

3.2. Cardiac catheterization before and after surgery
Emax and the maximal LV dp/dt increased after surgery. The LV end-diastolic pressure, minimum LV dp/dt, and {tau} decreased after surgery. The values measured by the catheterization were summarized in Table 2 and there was a significant difference between values before and after surgery.


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  		Table 2. Cardiac catheterization data before and after surgery
 
Systolic function of LV improved after surgery without compromising diastolic function. In addition, the surgical technique used in the present study avoided excessive volume reduction of the left ventricle.

3.3. Serial echocardiographic change after surgery
Thirty-five rats underwent LV volume reduction surgery and 24 rats survived surgery. In 16 rats LVR was properly carried out and the efficacy of the surgery was confirmed by echocardiography and cardiac catheterization. Among them, 12 rats survived 4 weeks after surgery and were subjected to serial echocardiographic follow-up completely.

Comparing LV dimensions at 4 weeks after surgery with those at baseline, rats were divided into two groups as follows. One was Good result group, of which LV dimension at 4 weeks after surgery remained smaller than that at baseline. The other was Poor result group, of which LV dimension at 4 weeks after surgery became larger than that at baseline. LV Dd of Poor result group increased quicker and more severely than that of Good result group, as shown in Fig. 1.



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  		Fig. 1. (A) and (B) Serial echocardiographic change of cardiac function after surgery. (A) Change of left ventricular end-diastolic dimension (LV Dd): LV dimension once reduced by surgery increased time by time. LV redilatation of Bad result group was much more intense than that of Good result group. (B) Change of fractional shortening (FS): LV function once improved by surgery deteriorated time by time. LV function of Bad result group was more deteriorated than that of Good result group. *P<0.05, +P<0.001 vs. Poor group.

 
The dimension of the left ventricle was uniformly reduced by surgery, following progressive redilatation time by time. LV Dd and LV Ds in Poor result group increased more quickly and severely than those in Good result group, as shown in Table 3 and Fig. 1. Similarly, FS and FAC of LV increased uniformly after surgery in both groups, following progressive deterioration time by time. FS and FAC of Poor result group deteriorated quicker and more severely than those of Good result group as shown in Table 3.


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  		Table 3. Serial echocardiographic change after surgery
 
3.4. Histological study
3.4.1. Control DCM rats
Fractional fibrosis calculated as percent fibrosis varied widely from 4.4 to 45.2% part by part and localization of fibrosis varied. In the present model of DCM, fibrosis scattered around and localization of fibrosis differed rats by rats as shown in Table 4. The most fibrotic parts of each individual hearts differed rats by rats. The anterior part was the most fibrotic in one of 6 rats, the septum in 2, the posterior in one, and the lateral in 2. The anteroseptal wall was more fibrotic than posterolateral wall in 3 of 6 rats and the posterolateral wall was more fibrotic than the anteroseptal wall in 3. The LV wall of the DCM rats was not homogeneously damaged as shown in Fig. 2.


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  		Table 4. Histological data of control DCM rats
 


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  		Fig. 2. Masson's trichrome staining of transected LV. In this specimen, fibrosis distributes prominently in the lateral wall. The lateral wall is more fibrotic than the anteroseptal wall. Fibrosis is not diffusely scattered and localized in the lateral wall.

 
3.4.2. Four weeks after surgery
Percent fibrosis of the septum, which was far from surgical site and presumably least damaged by surgery itself, in Good result group was significantly smaller than that in Poor result group (11.3±3.4 vs. 27.8±2.8%, P<0.0001). Regarding percent fibrosis of the rest of the heart, which consisted of the anterior part and the posterior part, there was no big difference between both groups (14.9±4.9 vs. 22.7±8.1%, P=0.07).

Comparing the relationship between the ratio of LV redilatation (delta redilatation) and percent fibrosis of the septum, there was a strong correlation recognized between them (r=0.951, P<0.001) as shown in Fig. 3.



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  		Fig. 3. The relationship between the ratio of LV redilatation and the fractional fibrosis in the septum. The more dilated LV dimension became after surgery, the more fibrotic the septum retained by surgery was. Delta redilatation was explained in the text.

 
The ratio of LV redilatation was calculated as follows; (LV Dd after–LV Dd before)/LV Dd beforex100 (%).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Result
 4. Discussion
5. Study limitations
 Appendix A. Conference...
 References
 
Dr Batista introduced the surgical concept of resecting sound muscle and reducing LV diameter in order to improve LV function of enlarged DCM hearts according to the physics [14]. This concept seemed attractive to treat end-stage heart failure and brought broad attention not only to the surgical community but also to the entire cardiovascular medicine. A short-term result of PLV to treat a difficult patient group of end-stage heart failure was good enough to convince many surgeons to start performing PLV. However, unpredictable and inconsistent mid-term results have gradually been revealed and the initial hope to PLV has diminished quickly [1,2].

In 1996 we started performing PLV for DCM and achieved good initial results, following unpredictable mid-term result as occurred similarly around the world. We examined LV wall motion thoroughly by echocardiography with utilizing color kinetic method before surgery and intraoperatively and we noticed some patients had abnormal regional wall motion [5,6]. Abnormal LV wall motion and heterogeneity of LV wall property in DCM was pointed out previously [3,4]. According to the echocardiographic findings, we started SAVE operation, septal anterior ventricular exclusion, instead of PLV when LV wall motion of the anteroseptal part was worse than that of the posterolateral part [15,16]. Then left ventriculoplasty for DCM by careful selection of PLV and SAVE improved a mid-tem result. Four year survival rate of 61 elective operations was 69.3% [17].

In the present study, we adopted a DCM model created by means of autoimmunization with cardiac myosin because this model type is mimicked with humane DCM without hypertension [7,8]. Histological study showed that localized fibrosis scattered in the left ventricle and location of fibrosis differed individually. This means that the LV wall in this DCM model has inhomogeneous histology, and that the model is suitable for evaluating the relationship between LV wall property and the surgical result.

The findings of the present study are summarized as follows. Echocardiography and cardiac catheterization confirmed the efficacy of the surgery, but LV diameter which had been reduced right after the surgery had gradually enlarged as time passed. The ratio of LV redilatation differed in two groups. Half of animals remained in good shape with smaller LV dimension than baseline, and the other half deteriorated in bad shape with larger LV dimension. Histological study showed the fraction of residual fibrosis in Good result group was significantly less than that in Bad result group. There was a strong correlation between the ratio of LV redilatation and the relative amount of residual fibrosis.

This study infers that localization of fibrosis affects the long-term result of PLV. Decreasing number of heart transplantation around the world, there seeks a possibility of non-transplant surgery for end-stage heart failure. Initial experience of PLV has left a fact that PLV could salvage some candidates for heart transplantation to a considerable extent in spite of denying the almightiness of PLV [2]. We must consider not only resecting the posterolateral wall like PLV but also some intervention to the anteroseptal wall such as SAVE operation depending on the patients' LV wall property. Such a strategic approach as a combination of resecting damaged myocardium and retaining sound muscle can improve a long-term result of LV restoration surgery for DCM.

In conclusion, a long-term result of LV volume reduction surgery for DCM rats was affected by the amount of residual fibrosis. This information suggests that proper selection of the surgical site is important to achieve a good result of LV restoration surgery for DCM.


   5. Study limitations
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Result
 4. Discussion
 5. Study limitations
Appendix A. Conference...
 References
 
This study was conducted as a retrospective analysis to examine the result of the surgery. We can conduct the study prospectively if we recognized the LV wall property exactly before surgery. In the present time we have no reliable tool to examine the interstitial fibrosis of the whole heart without excising the heart for pathological examinations. Alternatively we sacrificed 6 DCM rats before surgery for histological study, which confirmed that they had wide variety of LV wall property in terms of myocardial fibrosis.

Further development of the technology may help to detect the LV wall property exactly and predict the result of the surgery prospectively.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Result
 4. Discussion
 5. Study limitations
 Appendix A. Conference...
References
 
Dr R. Poston (Baltimore, MD, USA): The hearts that did bad, did they have more overall inflammation, or was it localized to the septum?

Dr Horii: I don't follow you.

Dr Poston: It is possible that there is just overall more myocardial inflammation and fibrosis that also included the septum in the hearts that did bad which was not necessarily specific to the septum. If that's the case, it could just be that in your model a bad heart outcome is due mainly to a more intense inflammatory response from the autoimmune stimulus. Irregardless of the ventricular surgery, the inflammatory response led to the hearts dilating back out.

Dr Horii: Unfortunately, I don't have a good answer for you, because I cannot tell you if such a fibrosis is the reason or is the cause.

Regarding myocardial fibrosis, the septum was the least damaged by surgery itself and the least fibrotic portion as shown in my presentation. And even in the clinical setting and also in this experimental setting, there was localized fibrosis and heterogeneity of LV wall in DCM hearts. And so, LV surgery can be performed in an appropriate way to treat DCM hearts.


   Footnotes
 
☆ Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Result
 4. Discussion
 5. Study limitations
 Appendix A. Conference...
 References
 

  1. Gorcsan 3rd J, Feldman AM, Kormos RL, Mandarino WA, Demetris AJ, Batista RJ. Heterogeneous immediate effects of partial left ventriculectomy on cardiac performance. Circulation 1998;97:839-842.[Abstract/Free Full Text]
  2. Franco-Cereceda A, McCarthy PM, Blackstone EH, Hoercher KJ, White JA, Young JB, Starling RC. Partial left ventriculectomy for dilated cardiomyopathy: is this an alternative to transplantation?. J Thorac Cardiovasc Surg 2001;121:879-893.[Abstract/Free Full Text]
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  5. Suma H, Isomura T, Horii T, Sato T, Kikuchi N, Iwahashi K, Hosokawa J. Nontransplant cardiac surgery for end-stage cardiomyopathy. J Thorac Cardiovasc Surg 2000;119:1233-1244.[Abstract/Free Full Text]
  6. Isomura T, Suma H, Horii T, Sato T, Kikuchi N. Partial left ventriculectomy, ventriculoplasty or valvular surgery for idiopathic dilated cardiomyopathy—the role of intra-operative echocardiography. Eur J Cardiothorac Surg 2000;17:239-245.[Abstract/Free Full Text]
  7. Kodama M, Hanawa H, Saeki M, Hosono H, Inomata T, Suzuki K, Shibata A. Rat dilated cardiomyopathy after autoimmune giant cell myocarditis. Circ Res 1994;75:278-284.[Abstract/Free Full Text]
  8. Hirono S, Islam MO, Nakazawa M, Yoshida Y, Kodama M, Shibata A, Izumi T, Imai S. Expression of inducible nitric oxide synthase in rat experimental autoimmune myocarditis with special reference to changes in cardiac hemodynamics. Circ Res. 1997;80:11-20.[Abstract/Free Full Text]
  9. Okura Y, Yamamoto T, Goto S, Inomata T, Hirono S, Hanawa H, Feng L, Wilson CB, Kihaya I, Izumi T, Shibata A, Aizawa Y, Seki S, Abo T. Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats. J Mol Cell Cardiol 1997;29:491-502.[CrossRef][Medline]
  10. Nishina T, Nishimura K, Yuasa S, Miwa S, Nomoto T, Sakakibara Y, Handa N, Hamanaka I, Saito Y, Komeda M. Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model. Circulation 2001;104:I241-I245.
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  12. Tambara K, Sakakibara Y, Sakaguchi G, Lu F, Premarantne GU, Lin X, Nishimura K, Komeda M. Transplanted skeletal myoblasts can fully replace the infracted myocardium when they survive in the host in large numbers. Circulation 2003;108:II259-II263.
  13. Koyama T, Nishimura K, Unimonh O, Ueyama A, Komeda M. Importance of preserving the apex and plication of the base in left ventricular volume reduction surgery. J Thorac Cardiovasc Surg 2003;125:669-677.[Abstract/Free Full Text]
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