Ann Thorac Surg 1999;67:1714-1720
© 1999 The Society of Thoracic Surgeons
Original Articles
Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium
G. Chad Hughes, MDa,
Alan P. Kypson, MDa,
James D. St. Louis, MDa,
Brian H. Annex, MDb,
R. Edward Coleman, MDc,
Timothy R. DeGrado, PhDc,
Carolyn L. Donovan, MDb,
James E. Lowe, MDa,
Kevin P. Landolfo, MDa
a Divisions of Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
b Division of Cardiology, Duke University Medical Center, Durham, North Carolina, USA
c Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
Accepted for publication December 31, 1998.
Address reprint requests to Dr Landolfo, Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Box 3857, Durham, NC 27710
e-mail: Land001{at}mc.duke.edu
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Abstract
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Background. Transmyocardial laser revascularization (TMR) has been demonstrated effective for relieving angina, although prior studies have yielded inconsistent results regarding postoperative myocardial perfusion and function. This study evaluated long-term changes in myocardial perfusion and contractile reserve after TMR in a model of hibernating myocardium.
Methods. Miniswine had subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, positron emission tomography and dobutamine stress echocardiography were performed to document ischemic, viable (hibernating) myocardium in the left circumflex distribution. Animals then had sham redo thoracotomy (n = 4) or TMR (n = 6). Six months later the positron emission tomography and dobutamine stress echocardiography studies were repeated.
Results. Myocardial blood flow in the left circumflex distribution as measured by positron emission tomography was significantly reduced in all animals after 2 weeks in the low-flow state. In animals that had TMR, there was significant improvement in myocardial blood flow to the lased regions 6 months postoperatively. No significant change in myocardial blood flow was seen in sham animals at 6 months. Dobutamine stress echocardiography after 2 weeks of low-flow demonstrated severe hypocontractility at rest in the left circumflex region of all animals, with a biphasic response to dobutamine consistent with hibernating myocardium. In animals that had TMR, there was a trend toward improved resting function and significantly improved regional stress function in the lased segments 6 months postoperatively, consistent with a reduction in ischemia. Global left ventricular wall motion at peak stress improved significantly as well. There was no change in wall motion 6 months postoperatively in sham-operated animals.
Conclusions. This study found improvements in myocardial perfusion and regional and global contractile reserve 6 months after TMR in a porcine model of hibernating myocardium. This improved perfusion and function likely accounts for the clinical benefits of the procedure.
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Introduction
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Transmyocardial laser revascularization (TMR) is an emerging technique to treat end-stage coronary artery disease. The technique has improved anginal symptoms in up to 75% of treated patients [1–5]. However, studies showing a clinical benefit from TMR have not demonstrated a consistently significant improvement in myocardial perfusion postoperatively [1, 2, 5]. In addition, a recent experimental study suggested that the angina relief after TMR might result from myocardial denervation without a change in perfusion [6].
To date, no experimental study has addressed specifically the long-term changes in myocardial perfusion and function after TMR. Because of the dearth of experimental data, as well as the inconsistent findings of clinical studies regarding post-TMR myocardial perfusion, we studied that issue in an experimental setting. We evaluated myocardial perfusion by positron emission tomography (PET) and contractile reserve by dobutamine stress echocardiography (DSE) 6 months after TMR in a porcine model of ischemic, viable (hibernating) myocardium to determine the effects of TMR on myocardial blood flow and regional and global wall motion at rest and with stress.
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Material and methods
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A total of 10 adult male mini-swine (30 kg) were used. Animals were obtained from Harlan-Sinclair (Indianapolis, IN) and housed under standard conditions and fed a regular diet. The Animal Care and Use Committee of Duke University approved all procedures and protocols. Animals received humane care in compliance with the "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 of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Model of hibernating myocardium
Anesthesia was induced with ketamine (22 mg/kg intramuscularly) and thiopental (5 to 10 mg/kg intravenously). Orotracheal intubation was performed and anesthesia maintained with isoflurane (2% to 4%) while the animals were mechanically ventilated. Continuous electrocardiographic and pulse-oximetric monitoring was used throughout the procedure to ensure a stable cardiac rhythm and adequate oxygenation. Cefazolin (1 g intravenously) and lidocaine (1.5 mg/kg intravenously) were given preoperatively. Under sterile conditions, a left anterolateral thoracotomy was done through the fourth intercostal space. The pericardium was incised longitudinally, and the left atrial appendage retracted to allow exposure of the left circumflex (LCX) coronary artery. The proximal LCX was dissected free to allow placement of a hydraulic occluder and 2-mm ultrasonic flow probe (Transonic Systems Inc, Ithaca, NY) around the vessel. The flow probe was placed distal to the occluder to record downstream flow through the LCX (Fig 1). The pericardium was closed. The occluder and flow probe were then exteriorized through a separate stab incision. A 20-F chest tube was placed and the wound closed in layers. The chest tube was removed at the conclusion of the procedure. Three days postoperatively the occluder was inflated to reduce resting blood flow in the LCX to approximately 10% of baseline as assessed by the implanted flow probe. The animals were then kept in this low-flow state with blood flow recordings made three times per week to assure continued occlusion. A prior study using this model [7] demonstrated ischemic, viable (hibernating) myocardium in the LCX distribution by positron emission tomography (PET) and dobutamine stress echocardiography (DSE). Triphenyl-tetrazolium chloride staining demonstrated a mean of only 8% ± 2% infarction of the area-at-risk at the endocardial surface. This chronic hibernation was stable for over 1 month postoperatively as assessed by follow-up PET and DSE.
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Fig 1. Coronary angiogram showing experimental preparation. Note normal left anterior descending coronary artery (curved arrow), proximal partial occlusion of the left circumflex coronary artery (straight arrow) at the site of hydraulic occluder placement (radiolucent and not visualized), and flow probe (open arrow) located downstream from the occluder on the left circumflex artery.
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Pre-transmyocardial laser revascularization positron emission tomography and dobutamine stress echocardiography
After 2 weeks in the low-flow state, animals underwent positron emission tomography and dobutamine stress echocardiography to characterize the blood flow, metabolic, and functional status of the heart and to document the presence of hibernating myocardium in the LCX distribution. PET scans were interpreted as showing hibernating myocardium if a flow deficit was noted in the lateral and posteroinferior walls of the left ventricle supplied by the LCX accompanied by normal or increased glucose utilization in these same regions (both as compared with the nonischemic septum) [8]. Using DSE, we defined viability in the lateral and posteroinferior walls of the left ventricle as an improvement in systolic wall thickening with low-dose dobutamine in myocardial regions with severe hypocontractility at rest. Viable segments were considered ischemic if systolic wall motion deteriorated with stress (biphasic response) [9, 10].
Dobutamine stress echocardiography
DSE was performed in 3-minute stages with incremental doses of dobutamine beginning with 5 µg/kg per minute and increasing to 40 µg/kg per minute. Based on a standard 16-segment model, wall motion was graded as 1 = normal, 2 = hypokinetic (reduced systolic wall thickening), 3 = akinetic (absent systolic wall thickening), and 4 = dyskinetic (outward systolic wall motion). Regional and global wall motion score indices (WMSI) were calculated at rest, with low-dose dobutamine, and at peak stress. Animals were sedated with ketamine (22 mg/kg intramuscularly) before DSE. The echocardiograms were interpreted by a cardiologist (C.L.D.) with expertise in stress echocardiography who was blinded to the clinical status of the swine.
Positron emission tomography
After an overnight fast, dynamic PET imaging of the heart was performed at rest for 20 minutes after a 30-second intravenous infusion of 13N-ammonia (15 to 20 mCi). A 40-minute delay followed for decay of 13N activity. Then dynamic imaging of the heart for 60 minutes was performed after a 30-second infusion of 18F-fluorodeoxyglucose (10 mCi). All emission images were corrected for photon attenuation using a transmission scan. Time-activity curves of tracer concentration in the left ventricular myocardium were obtained from short-axis views averaged over eight sectors in three short-axis slices (basal, mid, and apical) (Fig 2). Previously validated compartmental modeling techniques were applied to the time-activity curves to obtain regional estimates of myocardial blood flow (mL/g per minute) and glucose utilization (nmol/g per minute) [11, 12]. A lumped constant of 1.0 was assumed for the calculation of glucose utilization from fractional 18F-fluorodeoxyglucose uptake rate [13]. During the PET scans, animals were maintained under general anesthesia and mechanically ventilated as described above. PET scans were interpreted in a blinded manner both qualitatively by a physician (R.E.C.) experienced in reading cardiac PET scans and quantitatively using absolute values for blood flow (mL/g per minute) and glucose utilization (nmol/g per minute).
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Fig 2. Diagram of the 8 sectors used for comparing quantitative measurements of myocardial blood flow and glucose utilization in the three short-axis slices (basal, mid, and apical). Sectors 2 through 4 (lateral and posteroinferior walls of the left ventricle [LV]) were considered as representing myocardium within the left circumflex distribution. Sectors 7 and 8 served as the nonischemic control regions.
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Transmyocardial laser revascularization
Once hibernating myocardium in the LCX distribution was documented by PET and DSE, six randomly chosen animals had repeat anterolateral thoracotomy through the fifth intercostal space. The operation was performed within 3 days of completion of baseline studies. Anesthesia, preoperative medications, and intraoperative monitoring were as described above. A holmium:yttrium-aluminum-garnet (YAG) laser (Cardiogenesis Inc, Sunnyvale, CA) (n = 4) or 800-W carbon dioxide (CO2) laser (PLC Medical Systems Inc, Milford, MA) (n = 2) was used to create 20 channels at 1-cm intervals in the ischemic regions of the left ventricle as demonstrated on DSE and PET. Care was taken to avoid all epicardial and intramyocardial vessels. CO2 laser channels were created using a single 40-J pulse, whereas holmium:YAG channels were created using multiple 2-J pulses, with a total energy level of approximately 20 J per channel. Transmural penetration of laser channels was confirmed by visible spurting of blood from the channels during systole. Hemostasis was obtained by manual compression. The occluder and flow probe were left intact. The pericardium was left widely open. The wound was closed as described above. Continuous LCX occlusion was confirmed postoperatively by weekly flow monitoring with the flow probe.
Sham thoracotomy
After PET and DSE studies demonstrating hibernating myocardium in the LCX region, four randomly chosen animals had repeat anterolateral thoracotomy through the fifth intercostal space as a sham procedure. The operation was performed within 3 days of completion of baseline studies. Anesthesia, preoperative medications, and intraoperative monitoring were as described above. The pericardium was opened but TMR was not done. The occluder and flow probe were left intact. The pericardium was left widely open. The wound was closed as described above. Continuous LCX occlusion was confirmed postoperatively by weekly flow monitoring with the flow probe.
Follow-up positron emission tomography and dobutamine stress echocardiography
Six months after the second operation (TMR or sham redo thoracotomy), animals had repeat PET and DSE as described above. To allow comparisons between studies performed at baseline and 6 months postoperatively and to correct for the known interstudy variability of absolute values of myocardial blood flow and glucose utilization obtained by PET [11, 14], the data were normalized using previously described techniques [14]. For each study, sectors representing the anterior septum (sectors 7 and 8 in Fig 2) were used as the normal reference segments. 13N-ammonia activity in the sectors representing the LCX distribution (sectors 2 to 4 in Fig 2) were then expressed as a percentage of the activity measured in the reference segments. Relative segmental 18F-fluorodeoxyglucose uptake was assessed using the identical method, with a value of 100% given to the anteroseptal reference segments.
Statistical analysis
Data were analyzed using STATISTICA for Windows version 5.1 (StatSoft Inc, Tulsa, OK). All data are presented as the mean ± standard error of the mean. Myocardial blood flow and glucose utilization by PET, as well as wall motion scores by DSE, were compared within groups using a paired Student’s t test. Between-group comparisons were performed using a one-way analysis of variance. Statistical significance was considered a p value less than 0.05.
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Results
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Baseline PET perfusion images in all animals showed decreased 13N-ammonia accumulation in the lateral and posteroinferior wall myocardium and normal to increased 18F-fluorodeoxyglucose accumulation in the area of perfusion abnormality consistent with hibernating myocardium (Fig 3) [8]. Quantitative measurement of baseline myocardial blood flow by PET showed a highly significant decrease in myocardial perfusion to the basal, mid, and apical lateral and posteroinferior walls of the left ventricle supplied by the partially occluded LCX coronary artery compared with the corresponding nonischemic septal regions (Table 1). Myocardial viability was confirmed by the finding of preserved to increased glucose utilization in the regions of decreased blood flow [8] compared with the corresponding control septal regions (Table 2).
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Fig 3. Representative baseline positron emission tomography 13N-ammonia (13NH3) perfusion scan (top left) showing a flow defect in the lateral and posteroinferior walls of the left ventricle as seen on the short axis view. Corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake scan (top right) showing a relative increase in glucose utilization in the region of the flow defect consistent with preserved myocardial viability. Corresponding post transmyocardial laser revascularization (TMR) positron emission tomographic scan from the same animal. Note the increase in 13N-ammonia accumulation in the lased left circumflex distribution 6 months postoperatively (bottom left), consistent with increased blood flow. There is more homogeneous 18F-fluorodeoxyglucose uptake (bottom right) associated with this improvement in blood flow.
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Analysis of PET perfusion images 6 months after TMR showed increased 13N-ammonia accumulation in the lateral and posteroinferior wall myocardium, consistent with improved blood flow to the lased regions. In addition, there was no longer a qualitative mismatch between 13N-ammonia and 18F-fluorodeoxyglucose accumulation in the LCX distribution, also consistent with reduced ischemia [8] (Fig 3). Normalized myocardial perfusion (Table 3) for the lased basal, mid, and apical lateral and posteroinferior walls of the left ventricle (Fig 4) was significantly higher than pre-TMR values, reflecting improved myocardial blood flow to these regions 6 months after treatment with TMR.
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Table 3. Normalized Myocardial Perfusiona by Positron Emission Tomography for Left Circumflex Artery Distributionb Preoperatively and 6 Months Postoperatively in Animals That Had Transmyocardial Laser Revascularization (n = 6) and Sham Redo Thoracotomy (n = 4)
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Fig 4. Normalized left circumflex artery distribution blood flow by positron emission tomography for base, mid, and apex before and 6 months after transmyocardial laser revascularization (TMR). There is a significant increase in myocardial blood flow to the lased left circumflex artery regions 6 months after transmyocardial laser revascularization.
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Analysis of PET perfusion images 6 months after sham redo thoracotomy revealed a persistent decrease in 13N-ammonia accumulation in the lateral and posteroinferior wall myocardium similar to that seen at baseline. Likewise, there was no significant change in normalized myocardial perfusion (Table 3) for the basal, mid, and apical LCX regions 6 months after the sham procedure.
Baseline DSE demonstrated severe hypocontractility at rest in the lateral and posteroinferior walls of the left ventricle supplied by the partially occluded LCX coronary artery. Wall motion in these regions demonstrated a biphasic response of initial improvement followed by deterioration with dobutamine stimulation (Table 4), which is consistent with ischemic, viable myocardium in the LCX distribution. Six months after TMR (Table 4), there was a trend toward improved resting wall motion and a significant improvement in regional WMSI for the lased segments at peak stress (Figs 5 and 6). Global WMSI for the entire left ventricle at rest after TMR was unchanged (Table 5), but global WMSI during high-dose dobutamine infusion improved significantly from pre-TMR levels, which is consistent with a reduction in ischemia during stress (Fig 7).
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Table 4. Mean Regional Wall Motion Score Indexa Preoperatively and 6 Months Postoperatively for Animals That Had Transmyocardial Laser Revascularization (n = 6) and Sham Redo Thoracotomy (n = 4)
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Fig 5. Representative short axis echocardiographic view of the left ventricle during peak dobutamine stress before transmyocardial laser revascularization (TMR) (left) showing an inferoposterolateral ischemic wall motion abnormality. The post-transmyocardial laser revascularization image (right) shows resolution of the wall motion abnormality. Arrows denote endocardial surface. PM = location of papillary muscles in each image.
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Fig 6. Mean regional wall motion score index (WMSI) (1 = normal; 2 = hypokinetic; 3 = akinetic; 4 = dyskinetic) at rest, low stress, and peak stress for the lateral and posteroinferior walls of the left ventricle before and 6 months after treatment with transmyocardial laser revascularization (TMR). Note the trend toward improved resting function and the significant improvement in regional wall motion score index at peak stress 6 months after transmyocardial laser revascularization.
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Table 5. Mean Global Wall Motion Score Indexa Preoperatively and 6 Months Postoperatively for Animals That Had Transmyocardial Laser Revascularization (n = 6) and Sham Redo Thoracotomy (n = 4)
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Fig 7. Mean global wall motion score index (WMSI) (1 = normal; 2 = hypokinetic; 3 = akinetic; 4 = dyskinetic) at rest, low stress, and peak stress for all 16 left ventricular segments before and 6 months after transmyocardial laser revascularization (TMR). Note the significant improvement in global wall motion score index at peak stress 6 months after transmyocardial laser revascularization.
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For animals that had sham redo thoracotomy, baseline wall motion in the lateral and posteroinferior left ventricular walls demonstrated severe hypocontractility at rest, as seen in the group of animals randomized to TMR. As in the animals that had TMR, a biphasic response to dobutamine consistent with ischemic, viable myocardium was present as well (Table 4). Six months after the sham procedure, there was no significant change in resting or peak-stress regional WMSI (Table 4). Likewise, global WMSI for the entire left ventricle at rest and during high-dose dobutamine infusion were unchanged as well (Table 5).
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Comment
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Transmyocardial laser revascularization is emerging as a potential treatment strategy for thousands of patients with ischemic heart disease not amenable to coronary artery bypass grafting or percutaneous angioplasty. In this study we found increased myocardial perfusion by PET and improved functional outcome by DSE in areas of hibernating myocardium 6 months after treatment with TMR. This improved myocardial perfusion and stress function (contractile reserve) after TMR likely explains the clinical benefits of the procedure. These functional improvements were seen after TMR with holmium:YAG and CO2 lasers. Although the purpose of this study was not a direct functional comparison of holmium:YAG and CO2 lasers, there was no readily apparent difference in the degree of improvement seen with each laser.
There are no previous long-term experimental studies evaluating myocardial perfusion after TMR in hibernating myocardium, but there have been several short-term studies done using normal hearts. The first study to examine myocardial perfusion after TMR was done by Hardy and colleagues [15], who found that endocardial blood flow, as assessed using radioactive microspheres, was actually decreased 10 minutes after laser treatment. Likewise, Whittaker and associates [16] found no increase in myocardial blood flow up to 5
hours after treatment when TMR channels were created 30 minutes after occlusion of the left anterior descending coronary artery. Kohmoto and colleagues found no increase in myocardial blood flow immediately [17] or 2 weeks [18] after TMR in normal canine hearts. Conversely, Whittaker and associates [19] in a later study found that TMR channels made 2 months before coronary occlusion led to a decrease in infarct size, thus indirectly providing evidence for improved perfusion. However, unlike the present study, none of those investigations determined whether TMR increases myocardial perfusion over time in hibernating myocardium, the condition under which the technique is applied clinically [1–5].
Clinical reports of TMR have shown conflicting results with regard to changes in postoperative perfusion as well. In Mirhoseini and associates’ [20] early reported series of 12 patients who had combined coronary artery bypass grafting and TMR, thallium stress tests performed 3 months postoperatively consistently showed improved perfusion in the areas revascularized by laser. Likewise, Horvath and associates [3, 4] found improved perfusion in lased segments by technetium 99m and thallium 201 single photon emission computed tomography (SPECT) scanning 3 to 12 months after TMR. In contrast, Frazier and colleagues [1] and Cooley and colleagues [2] found no improvement in the transmural perfusion of lased segments by thallium 201 SPECT or PET in a group of 21 patients 3 to 12 months after TMR. In addition, they found that during high-dose dobutamine infusion the WMSI of lased segments worsened compared with pre-TMR status, indicating a decrease in myocardial perfusion during stress. These findings contrast with those of Donovan and colleagues [10], who found a marked improvement in WMSI at peak stress in lased segments 3 and 6 months postoperatively. More recently, Milano and associates [5] found no significant change in myocardial perfusion at a mean follow-up of 10 months in a group of 16 patients who had TMR with a holmium:YAG laser.
This heterogeneity in clinical findings is likely explained by the fact that patients who had TMR have diffuse, severe coronary artery disease and generally have had prior revascularization procedures [1–5]. Consequently, the results of postoperative perfusion studies in human subjects may be confounded by a progression of native coronary disease, restenosis of prior angioplasty sites, or new disease in existing bypass grafts. For these reasons, the present study is useful in that it allows perfusion changes after TMR to be evaluated in an experimental model of isolated ischemia in the LCX distribution without the interference of confounding variables found in clinical studies. We believe these results prove that TMR increases myocardial perfusion in hibernating myocardium 6 months postoperatively.
A recent study found that TMR with a holmium:YAG laser denervated canine myocardium [6], and the authors suggested that denervation might be the therapeutic mechanism behind the procedure. The present study in no way refutes the possibility of myocardial denervation after TMR. However, it does show that myocardial perfusion improved 6 months postoperatively. In addition, we would strongly speculate that this increased perfusion, rather than denervation, is the mechanism responsible for decreased angina in the months after the procedure. This improvement in myocardial perfusion appears to be delayed, as supported by the findings of multiple experimental studies failing to detect any short-term increase in myocardial perfusion after TMR [15–18] and is likely secondary to neovascularization [21]. We recently found evidence for angiogenesis 6 months after TMR in hibernating myocardium using the same experimental model presented here [22]. However, because a few patients show an immediate reduction in anginal symptoms after the procedure, the contribution of denervation to this early improvement cannot be discounted.
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Acknowledgments
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This work was supported in part by a National Research Service Award from the National Institutes of Health and the National Heart, Lung, and Blood Institute (grant no. 1 F32 HL09969-01) (G. C. Hughes). We thank Michael Lowe for surgical technical assistance, John Toptine for technical assistance with dobutamine stress echocardiography, and Sharon Hamblen, Mary Traynor, and Al Moore for technical assistance with positron emission tomography.
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Footnotes
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This work was supported in part by research contributions, as well as unrestricted educational grants from Cardiogenesis Inc (Sunnyvale, CA) and PLC Medical Systems Inc (Milford, MA).
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References
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Abstract
Introduction
