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Eur J Cardiothorac Surg 2004;26:89-95
© 2004 Elsevier Science NL

Factors excercising an influence on recovery of hibernating myocardium after coronary artery bypass grafting

^a Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum, Berlin, Germany
^b Department of Nuclear Medicine and Radiology, Charite, Campus Virchow Clinic, Humboldt University Berlin, Berlin, Germany

Received 24 October 2003; received in revised form 8 March 2004; accepted 15 March 2004.

^* Corresponding author. Address: Deutsches Herzzentrum Berlin, Augustenburgerplatz 1, Berlin 13353, Germany. Tel.: +49-30-4593-1000/2036; fax: +49-30-8867-5196
e-mail: hhausmann{at}dhzb.de

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
Objective: Coronary artery bypass grafting (CABG) in patients with endstage coronary disease (CAD) significantly improves symptoms and prolongs life expectancy. Left ventricular function is also improved in some patients, but not in others. Factors which influence functional recovery of hibernating myocardium after revascularization are at present under investigation. Methods: From 3/2000 to 8/2002, we analyzed 41 patients with an ejection fraction (EF) of 30%, who underwent CABG, prospectively. All patients received low-dose dobutamine echocardiography (DE), dobutamine myocardial scintigraphy with SPECT, dobutamine magnetic resonance tomography (MRI), contrast-enhanced MRI and, when necessary, positron emission tomography (PET). Hibernating myocardium (area of interest) was identified with these diagnostic tools preoperatively and biopsy samples were taken intraoperatively. Results: All patients received complete coronary revascularization. Early mortality was 2.4%. Three patients died during follow-up. Six months after the operation DE, MRI and SPECT were repeated. EF increased in 23 patients (group I) by at least 5%, and in 14 patients (group II) it did not improve. The wall motion score in the area of interest had increased during preoperative DE in group I significantly. The score did not change in group II. In addition the diastolic–systolic wall thickness increase in the area of interest rose >15% during DE in group I preoperatively; the increase was 15% in group II. MRI hyperenhancement of the left ventricle was significantly lower in group I compared to group II preoperatively. SPECT showed myocardial viability in the area of interest in all 37 patients. There were no significant differences between group I and II seen in SPECT. When the area of interest was located in the anterior wall the patients more frequently showed ventricular improvement postoperatively than patients with an area of interest located in the inferior, lateral or posterior wall. Light microscopy showed more severe myocardial cell hypertrophy (>19 µm) and less severe destruction of myocardial cell architecture in biopsies of group I compared to group II (myocardial cell hypertrophy 17 µm). Electron microscopy showed mitochondrial abnormalities in size and shape, lack of contractile material and large areas containing nonspecified cytoplasm, lipid droplets, and large glycogen-filled regions, but no significant differences between the two groups. Gene expresssion of the pro-apoptotic genes BAK and BAX was lowered compared to expression in ‘normal’ myocardium. The anti-apoptotic gene BCL-XL was significantly more expressed in the ‘area of interest’ of group II patients than in group I patients. Conclusions: We conclude that in patients with endstage CAD myocardial recovery after coronary revascularization can be predicted using DE and MRI preoperatively. Myocardial regions without any potential of functional recovery show less adaptation (less pronounced myocardial cell hypertrophy), a more severe degree of myocardial architecture destruction and a higher degree of anti-apoptotic gene expression. We recommend a myocardial biopsy when DE and MRI are not favorable in a patient with end stage coronary artery disease referred to us with the option of heart transplantation or coronary bypass.

Key Words: Hibernating myocardium • Coronary artery bypass grafting • Dobutamine echocardiography • Late-enhancement • Gene expression

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
The term ‘hibernating myocardium’, first introduced by Rahimtoola [1], refers to myocardium in a state of persistent dysfunction in the presence of coronary artery disease that may be reversed by revascularization. This may be an adaptive mechanism that preserves myocardial structural integrity and minimizes necrosis. The potential of functional myocardial recovery is most important in patients with left ventricular ejection fraction (LVEF) of less than 30%, who have already suffered myocardial infarction in the past [2]. However, surgical revascularization results demonstrate an improvement of left ventricular function in only a portion of these patients even though the clinical status also improves significantly in those who do not show a postoperative increase of LVEF [3]. Revascularization of patients with LVEF of <30% carries a higher risk than revascularization of patients with normal ventricular function, but survival in the short and long term has improved over the past decade in patients with endstage coronary artery disease receiving coronary artery bypass grafting (CABG) [4]. In comparison to mortality in medically treated patients, the mortality rate can be reduced by as much as 75% each year in these patients after CABG when viable myocardium can be demonstrated in preoperative investigations. No reduction of mortality was observed when myocardial viability was not shown before CABG [5].

The most effective diagnostic tool to identify chronically ischemic but viable myocardium, i.e. ‘hibernating’ myocardium, is under discussion, as are the factors which influence the degree of functional recovery of these myocardial segments of the left ventricle after CABG [6]. In some studies, the investigators used left ventricular myocardial biopsies taken intraoperatively in the area of hibernation to illuminate the problem. Nagueh et al. postulated that contractile reserve during low-dose dobutamine echocardiography (DE) preoperatively correlates inversely with the extent of interstitial fibrosis and the amount of fibronectin and vimentin and directly with rest-redistribution thallium uptake. Previous studies had several weaknesses. Selections of patients were nonuniform. Schwarz et al., for example, investigated patients with preoperative LVEF of 20–60%, Elsässer of 15–42% and Nagueh of 16–43%. Moreover, all biopsies were taken from the anterior wall only, meaning that the location of hibernating myocardium in the left chamber could not be analyzed. Extensive genetic investigations were missing [3,7,8]. The aim of this study was to analyze the factors influencing functional improvement after CABG of hibernating myocardium in a carefully selected group of patients with endstage coronary artery disease. The different diagnostic tools were validated in the context that today 8–10% of all patients who receive CABG have a preoperative LVEF of less than 30%.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
From March 2000 to August 2002, we prospectively analyzed 41 patients with LVEF 30% (mean of 26.0±7.7%) who underwent CABG. The average age was a mean of 63.6±9.9 years (36–82 years). Most of the patients were classified in NYHA class III preoperatively. Three patients were female and 38 male. A history of myocardial infarction followed by hospitalization of at least 3 days was documented in 78% of the patients preoperatively. Six patients (14.7%) suffered from more than one myocardial infarction preoperatively. Fourteen patients (34.2%) had a left main stenosis. More than two cardiac risk factors were present in 65.9% of the patients (Table 1) .

Table 2 shows our criteria for characterizing hibernating myocardium and other morphological states of the myocardium [9].

All patients received primary CABG procedure using a crystalloid cardioplegic solution and moderate hypothermia (32 °C) [2]. Left ventricular ‘venting’ was used routinely via the right pulmonary vein and the left atrium. The left or right mammary artery was used in combination with saphenous vein grafts. Transmural myocardial biopsies were obtained with a 20 mm 14-gauge Tru-cut biopsy needle at the time of bypass surgery but before cardioplegia. Transesophageal echocardiography was used to direct the needle to the selected myocardial segments. Three biopsies were acquired per patient from the area of interest. Biopsies were analyzed with light microscopy and electron microscopy and gene expression was measured in different classes such as pro- and antiapoptotic genes. Analysis of lightmicroscopy was performed with a semi-automatic software program (KS 400 Release 3.1) with a magnification of 200. The size of 25.070 myocardial cells was measured. All cells were classified in four different size-classes (under 15, 15.1–17, 17,1–19, >19 µm). The class of each probe was determined by the size of more than 50% of cells per field. When such a classification was impossible a destruction of myocardial cell architecture was documented.

Total RNA was extracted from left ventricular biopsies of hibernating areas or control tissues (from explanted donor hearts for heart transplantation) using Qiagen MiniPrep Reagents (Qiagen, Hilden, Germany) according to the manufacturer's protocol. Quality and quantity of RNA was controlled by OD 260/280 nm measurements and Bioanalyser RNA Chip technology (Bioanalyser Agilent 2100, Agilent Technologies, Inc., Böblingen, Germany). For first strand, cDNA synthesis a maximum amount of 1 µg of total RNA was denaturated with 1 µg random hexomer (50 µM) (Roche, Mannheim, Germany) for 10 min at 70 °C, followed by incubation on ice for 1 min. Reverse transcription was carried out in a mixture containing 4 µl 5x first strand buffer (Life Technologies Inc., Grand Island, NY, USA), 2 µl DTT (100 mM) (Life Technologies Inc.), 5 µl dNTP-mix (2 mM) (MPI Fermentas, St Leon-Rot, Germany) and 1 µl superscript II reverse transcriptase. Samples were incubated at 20 °C for 10 min and at 42 °C for 60 min. The reaction was stopped by heating to 70 °C for 15 min. Quantitative measurement of transcripts was performed using a GENEAmp5700 Sequence Detection System (PE Applied Biosystems, Überlingen, Germany) and a SYBR-Green Core Reagent Kit (PE Applied Biosystems) according to the manufacturer's protocol. Specific primer pairs were used to amplify the genes according to the standard PE PCR protocol (50 °C for 2 min, 95 °C for 10 min, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min). For each sample, quadruplets were run in the reaction and to avoid contamination, the AmpErase UNG reaction was performed using nucleotides containing dUTP. The reaction specificity was evaluated using a melting reaction (GeneAmp5700) and target gene expression was normalized to the expression of GADPH using the delta-delta-ct method after proving an efficiency of 100% for the reaction. Sequencing of the PCR products to verify amplification specificy was carried out according to the manufacturer's protocol using the Ampli-Taq FS Big Dye Terminator (PE Applied Biosystems). Gene expression was quantified by comparing the expressions in groups I and II with the expressions of the control group (explanted donor hearts for heart transplantation) in relative units.

The average length of follow up was 23±6 months with a range of 6–36 months. Postoperatively DE, MRI and SPECT were repeated after 6 months. Patients who showed an increase of LVEF at rest of 5% or more measured by echocardiography were assigned to group I and patients who did not show a significant increase to group II. All measured preoperative data of both groups were compared retrospectively.

All data were collected prospectively on standard forms and entered into a computerized database. Statistic analysis was performed with SAS and SPSS. All data were expressed as mean±standard deviation or as proportions. Qualitative differences between the ‘improving’ patients (group I) and the ‘non-improving’ patients were determined with the Mann–Whitney U-test. Comparisons of proportions were calculated using the -square test or Fisher's exact test. A p value <0.05 was considered statistically significant. Retrospectively demographic, clinical and operative data and the results of preoperative investigations were compared to find parameters to predict functional improvement in patients with highly reduced LVEF preoperatively.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
Operative mortality was 2.4% (1/41 patients). A 47-year-old female patient was lost due to septicemia after developing pneumonia early postoperatively. An average of 3.2±0.2 (range 1–4) grafts per patient was performed. Complete coronary revascularization was reached in 33 patients (80.5%), revascularization was incomplete in 8 patients (19.5%). Aortic clamp time was calculated to a mean of 55±8 min (range 31–69 min), cardiopulmonary bypass time reached an average of 112±11 min (range 78–132 min). An intra-aortic balloon pump (IABP) had to be implanted intraoperatively in 3 patients (7.3%); the IABP score [10] was 0 points in all three cases and the pump could be explanted on the second postoperative day after hemodynamic improvement in each case. Three patients died during the follow-up of 3 years. One patient suffered death after fatal cerebral stroke, another one was lost due to sudden cardiac death without having arrhythmias before. The third died after late development of pneumonia. All other patients were discharged home and were not re-submitted to the hospital for recurrent heart failure during follow-up.

Thirty-seven patients could be followed up and reexamined 6 months postoperatively. LVEF at rest measured with echocardiography increased from a mean of 27.3±2.1% (range 15–30%) to 36.1±1.4% (range 20–55%) in these patients (P<0.05). The increase of LVEF was 5% in 23 patients (group I), and less than 5% in 14 patients (group II). The left ventricular diastolic diameter decreased from a mean of 64.8±8.9 mm (range 49–91 mm) to 60.4±6.8 mm (range 43–80 mm) (P<0.05 s).

The area of interest was significantly more often located in the anterior wall (82.6%) in group I than in group II (57.1%).

Patients in group I had better coronary arteries. Eighteen (78.3%) of the 23 patients were assigned to class I according to the Kleikamp Classification [11]. Only 5 patients (35.7%) from group II could be assigned to class I (P<0.05) (Table 3) .

Furthermore, the wall motion score increase in group I was significant during DE preoperatively. This increase was less in group II.

Preoperative SPECT showed viability in the area of interest in both groups. The Pagley Score [12] was calculated to a mean of 14.2±0.7 points (range 6–20). Postoperatively a significant increase of the Pagley Score in all 12 segments of the left ventricle with a mean of 16.3±1.1 points (range 10–22) (P<0.01) was calculated, which describes an improvement of myocardial perfusion. Perfusion in the area of interest was also significantly improved (57.6±3.6 vs. 68.6±3.6%, P<0.05). Retrospective analysis of the preoperative SPECT examinations could not discriminate between patients of groups I and II.

This discrimination could be realized with our preoperative MRI investigations. MRI hyperenhancement was calculated to a mean of 16.7±11.6% (range 0–30%) of the left ventricle in group I compared to a mean of 27.4±14.4% (9–45%) in group II (P<0.05) (Table 3).

Light microscopy showed more severe myocardial cell hypertrophy (>19 µm) and less severe destruction of cell architecture in biopsies of group I than of group II (myocardial cell hypertrophy 17 µm) (Table 3).

Electron microscopy examinations of the tissue of the region of interest revealed slight degeneration with a loss of myofilaments and a slightly enlarged extracellular space. The empty myofilament areas were filled with glycogen deposits and mitochondria. Mitochondria in the spaces varied in size but were usually smaller and showed a thickening of the mitochondralic crest. We saw apoptosis in only two cases. We registered no significant differences between groups I and II with electron microscopy.

Measurements of gene expression showed significant depression of pro-apoptotic genes. Within the class, the pro-apoptotic BAK was down-regulated from 1.0±0.5 (controls) relative units to 0.5±0.3 in the hibernating probes (P<0.001). There was no statistical difference between groups I and II. But anti-apoptotic genes were significantly higher expressed in group II compared to group I (Table 3). Matrix metalloproteases, which catabolize cell proteins were 90% less expressed in samples of hibernating myocardium compared to normal samples. Within the calcineurin gene family, a significant difference was found for CAN-beta expression with an increase from 1.0±0.1 in the control group to 1.3±0.1 in all hibernation probes (P<0.05 s). There was no difference between groups I and II. Within the group of stress genes, there was significant increase in HSP 70-2 expression with 3.8±2.5 in the hibernation probes vs. 1.0±1.1 relative units in the control group (P=0.01 s).

The results of the retrospective analysis of the preoperative data to discriminate patients who will improve after CABG (group I) from those who will not (group II) are listed in Table 4 .

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

Our observations at the beginning of the past decade [2] that roughly two-thirds of these patients will show significant ventricular improvement after CABG and one third will not raised the question of whether this ventricular improvement can be predicted preoperatively. This question can now be answered in the affirmative. Our retrospective analysis of preoperative data demonstrates that stress echocardiography with determination of segmental left ventricular wall-thickness, motion and diastolic/systolic wall thickness increase and MRI measuring ‘late-enhancement’ are able to give a prediction of postoperative ventricular improvement. This confirms the observations of Leoncini et al. [17], Rose et al. [18] and Kim et al. [19] who have used DE and MRI as diagnostic tools for myocardial recovery in ischemic cardiomyopathy. Some authors have favored PET for detecting viable myocardium in end-stage CAD [20,21]. In our opinion PET, which was the ‘gold standard’ for many years, is too expensive and has the disadvantages that it needs time for preparation and cannot be used in the operating room. Echocardiography, on the other hand, can routinely be performed perioperatively; intraoperative observations can be compared to preoperative findings and can provide important information for the surgeon's intraoperative decisions. This opinion accords with the observations of Baer et al., who postulated that DE is a clinically valuable alternative to PET [22]. Shimoni and co-workers used myocardial contrast echocardiography and intraoperative myocardial biopsy to show that functional recovery correlates directly with microvascular density and inversely with the percentage of collagen content [23].

We were able to differentiate the ‘improving’ patients from the ‘non-improving’ patients not only with MRI and DE. Patients with smaller coronary arteries (caliber 2 mm) and diffuse coronary sclerosis [11] less often showed significant improvement after CABG in our study. This is not surprising, since the coronary arteries were the targets of our therapy.

Chronic ischemic left ventricular dysfunction is associated with profound structural alterations affecting both the cardiomyocytes and the interstitial space. There is a well-described loss of contractile material within the cardiomyocytes accompanied by a significant increase in extracellular matrix [24]. Elsässer et al. [7] described the accumulation of collagen fibrils and fibronectin in the widened interstitial space, suggesting that the combination of cellular degeneration and fibrosis may determine the degree and speed of recovery of dysfunctional segments after bypass surgery. Frangogiannis et al. [24] underlined the importance of the morphological characteristics of the cardiac interstitium in determining recovery of function after revascularization. They reported the deposition of tenascin, a matricellular protein transiently expressed in actively remodeling tissues, in the interstitium of hibernating segments. In addition, they described infiltration of the hibernating myocardium with phenotypically modulated myofibroblats producing Smemb, a marker activation. Their findings support the concept that ischemic myocardial dysfunction may be associated with a continuous, progressive fibrotic process, in which activated interstitial fibroblasts may have a prominent role through the production of extracellular matrix components. They concluded that the presence of active remodeling in hibernating myocardium appears to be an important process determining functional recovery after revascularization.

Our study has demonstrated for the first time that this active process has delicate gene regulation. We examined the expression of different gene classes and found that apoptotic, hypertrophic, matrix and stress genes participate in the regulation of hibernating myocardium in humans. For a long time this has only been demonstrated in animals [25]. In patients who showed a significant increase of LVEF postoperatively, expression of the anti-apoptotic gene BCL-XL was significantly lower than in patients without improvement of ventricular function after surgery. An explanation of this phenomenon may be that apoptosis has already started in the hibernating segments of the myocardium without postoperative recovery. Proapoptotic genes are excessively down-regulated in all hibernating areas. This is a distinct expression of the protective character of the regulation system in hibernating myocardium. The relation of cardiac gene expression as assessed by biopsy and quantitative techniques to the left ventricular function after surgery may provide a future tool to identify the benefit of coronary artery revascularization. Consequently, we recommend a myocardial biopsy when DE and MRI are not favorable in a patient with end stage coronary artery disease referred to us with the option of heart transplantation or coronary bypass.

	5. Conclusions

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
In patients with highly impaired left ventricular function recovery of hibernating myocardium can be predicted preoperatively with MRI and echocardiography with dobutamine stress. Patients with an area of interest located in the anterior wall and a good graftable left anterior descending coronary branch (diameter >1.5 mm) have the greatest potential for functional recovery after CABG. In patients with the lowest ejection fraction and no potential for myocardial recovery, heart transplantation should be considered. Hibernation is an active process with very delicate gene regulation. Patients with high expression of the antiapoptotic genes show less potential for myocardial recovery. These patients should be recommended for heart transplantation, despite other evidence that might favor CABG for these patients.

	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.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 
Dr P. Sergeant (Leuven, Belgium): The first two elements of your conclusion have been identified before; the most interesting one is maybe the last aspect about this gene expression. Are you suggesting that we should look into lesser invasive methods of taking biopsies of the left side of the heart to identify, based on the gene expression, patients that would benefit?

Dr Hausmann: Of course, in each coronary surgery department in the world, this patient group represents more than 10% of all coronary bypass patients. We can't perform a biopsy in all of these patients. We are doing such a case every day in Berlin, like in other centers.

I think this maybe makes sense in patients where we have the decision whether to transplant them or not, or maybe in a patient who had ventricular failure and we had to put such a patient on a mechanical assist device, and then during that procedure when you put in the mechanical assist device, we could perform a biopsy to see whether there is a genetic potential for myocardial recovery to think about placing this patient on a permanent device or to transplant him or maybe to wait for him for recovery.

Dr Sergeant: I would like to disagree partially. Any kind of evidence that we can build up, even before coronary surgery, that could avoid the patient to undergo coronary surgery would help us quite a lot. It is not just the decision of an assist device or transplantation.

Mr R. Ascione (Bristol, UK): Did you quantify the baseline presence of collaterals in the hibernated area? Presence of collaterals indeed might have improved the tolerance to the ischemic arrest and the recovery of segmental wall motion at midterm. In other words, is presence of collaterals the real predictor of recovery of hibernating myocardium?

Dr Hausmann: As we all know, many of these patients have occluded arteries, so many of these patients are alive or have the possibility to come to our operation room because they have collaterals, and the Kleikamp score published in the Annals this year has included these collaterals. Patients who showed improvement had good collaterals and patients who had no improvement after the operation had only poor collaterals and small coronary arteries. So the treatment of the patient is to give him a bypass, and of course, those patients who have a better situation for coronary artery bypass grafting are those who do improve.

Dr W. Mohl (Vienna, Austria): I don't understand the mechanism why the antiapoptotic gene BCL-XL should be more expressed in Group II, which is not going to improve.

Dr Hausmann: Yes. You mean the difference in the antiapoptotic gene?

Dr Mohl: Yes.

Dr Hausmann: I just can't speculate about the reason why this antiapoptotic gene is more increased in this Group II. Maybe the reason is that the apoptosis has come to a further stage in this Group II. You just have more apoptosis in these groups so the antiapoptotic gene is for protection again. As you remember, the table for all these gene regulations is for protection of the cell. Maybe these antiapoptotic genes are highly regulated for protection because in this group the apoptosis has reached a higher state than in the ones who showed improvement.

Dr Mohl: The differences in these gene expression levels are very low. Do you think that you have enough evidence that there was also no statistical significance?

Dr Hausmann: These are still small groups of patients, of course. I totally agree we have to analyze a higher number of patients.

Dr Mohl: Because the pro-inflammatory and the anti-inflammatory genes, they are upregulated to a much higher degree normally, you know, but in this respect you only saw a doubling of the gene expression levels, and this is not very far, that is not very much.

Dr Hausmann: But I really think we need a larger number of patients to answer that question.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A. Conference... References

 

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